Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors

ABSTRACT

Compounds of the formula Ia***** 
                         
in which the substituents have the definitions provided in the specification, are novel, effective PDE4 inhibitors, useful in the treatment of atopic eczema.

This application is a continuation application of Ser. No. 14/508,077,filed Oct. 7, 2014, which is a continuation application of Ser. No.13/873,670, filed Apr. 30, 2013, which is a continuation application ofSer. No. 13/661,897, filed Oct. 26, 2012, which is a continuationapplication of Ser. No. 13/111,544, filed May 19, 2011, which is acontinuation application of Ser. No. 10/590,803, filed Aug. 25, 2006,which was filed under 35 U.S.C. 371 as a national stage ofPCT/EP2005/050931, filed Mar. 2, 2005.

FIELD OF APPLICATION OF THE INVENTION

The Sequence Listing submitted in text format (.txt) filed on Aug. 25,2015, named “14508077-1 raw_SequenceListing.txt”, (created on Aug. 25,2015, 1 KB), is incorporated herein by reference.

The invention relates to novel hydroxy-6-heteroarylphenanthridinederivatives, which are used in the pharmaceutical industry for theproduction of pharmaceutical compositions.

KNOWN TECHNICAL BACKGROUND

The International Patent applications WO99/57118 and WO02/05616 describe6-phenylphenanthridines as PDE4 inhibitors.

In the International Patent application WO99/05112 substituted6-alkylphenanthridines are described as bronchial therapeutics.

In the European Patent application EP 0490823 dihydroisoquinolinederivatives are described which are said to be useful in the treatmentof asthma.

The International Patent application WO00/42019 discloses6-arylphenanthridines as PDE4 inhibitors.

The International Patent application WO02/06270 discloses6-heteroarylphenanthridines as PDE4 inhibitors.

The International Patent application WO97/35854 disclosesphenanthridines substituted in the 6-position as PDE4 inhibitors.

The International Patent applications WO2004/019944 and WO2004/019945disclose hydroxy-substituted 6-phenylphenanthridines as PDE4 inhibitors.

DESCRIPTION OF THE INVENTION

It has now been found that the novel 2- or3-hydroxy-6-heteroarylphenanthridines described in greater detail belowdiffer from the previously known compounds by unanticipated andsophisticated structural alterations and have surprising andparticularly advantageous properties.

The invention thus relates in a first aspect (aspect A) to compounds offormula I,

in which

-   R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,    or in which-   R1 and R2 together are a 1-2C-alkylenedioxy group,-   R3 is hydrogen or 1-4C-alkyl,-   R31 is hydrogen or 1-4C-alkyl,    either, in a first embodiment (embodiment a) according to the    present invention,-   R4 is —O—R41, in which-   R41 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or    predominantly fluorine-substituted 1-4C-alkyl, and-   R5 is hydrogen or 1-4C-alkyl,    or, in a second embodiment (embodiment b) according to the present    invention,-   R4 is hydrogen or 1-4C-alkyl, and-   R5 is —O—R51, in which-   R51 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or    predominantly fluorine-substituted 1-4C-alkyl,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a 5-    to 10-membered monocylic or fused bicyclic unsaturated or partially    saturated heteroaryl radical comprising 1 to 4 heteroatoms selected    independently from the group consisting of oxygen, nitrogen and    sulfur, in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, sulfanyl, cyano, 1-4C-alkoxycarbonyl, carboxyl,    hydroxyl, oxo, -A-N(R61)R62, pyridyl, or completely or partially    fluorine-substituted 1-4C-alkyl, in which-   A is a bond or 1-4C-alkylene,-   R61 is hydrogen or 1-4C-alkyl,-   R62 is hydrogen or 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which-   Het1 is optionally substituted by R611, and is a 3- to 7-membered    saturated or unsaturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one to three further heteroatoms independently selected    from the group consisting of oxygen, nitrogen and sulfur, in which-   R611 is 1-4C-alkyl,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, sulfanyl, hydroxyl, oxo, amino or mono- or    di-1-4C-alkylamino,-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy,    and the salts, the N-oxides and the salts of the N-oxides of these    compounds.

The invention further relates in a second aspect (aspect B), which is anembodiment of aspect A, to compounds of formula I,

in which

-   R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,    or in which-   R1 and R2 together are a 1-2C-alkylenedioxy group,-   R3 is hydrogen or 1-4C-alkyl,-   R31 is hydrogen or 1-4C-alkyl,    either, in a first embodiment (embodiment a) according to the    present invention,-   R4 is —O—R41, in which-   R41 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or    predominantly fluorine-substituted 1-4C-alkyl, and-   R5 is hydrogen or 1-4C-alkyl,    or, in a second embodiment (embodiment b) according to the present    invention,-   R4 is hydrogen or 1-4C-alkyl, and-   R5 is —O—R51, in which-   R51 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or    predominantly fluorine-substituted 1-4C-alkyl,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a 5-    to 10-membered monocylic or fused bicyclic unsaturated or partially    saturated heteroaryl radical comprising 1 to 4 heteroatoms selected    independently from the group consisting of oxygen, nitrogen and    sulfur, in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, cyano, 1-4C-alkoxycarbonyl, carboxyl, hydroxyl,    -A-N(R61)R62, pyridyl, or completely or partially    fluorine-substituted 1-4C-alkyl, in which-   A is a bond or 1-4C-alkylene,-   R61 is hydrogen or 1-4C-alkyl,-   R62 is hydrogen or 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which-   Het1 is optionally substituted by R611, and is a 3- to 7-membered    saturated or unsaturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one to three further heteroatoms independently selected    from the group consisting of oxygen, nitrogen and sulfur, in which-   R611 is 1-4C-alkyl,-   R7 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, 1-4C-alkylthio,    hydroxyl, amino or mono- or di-1-4C-alkylamino,-   R8 is halogen,    and the salts, the N-oxides and the salts of the N-oxides of these    compounds.

The invention further relates in a third aspect (aspect C), which is anembodiment of aspect A, to compounds of formula I,

in which

-   R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,    or in which-   R1 and R2 together are a 1-2C-alkylenedioxy group,-   R3 is hydrogen or 1-4C-alkyl,-   R31 is hydrogen or 1-4C-alkyl,    either, in a first embodiment (embodiment a) according to the    present invention,-   R4 is —O—R41, in which-   R41 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or    predominantly fluorine-substituted 1-4C-alkyl, and-   R5 is hydrogen or 1-4C-alkyl,    or, in a second embodiment (embodiment b) according to the present    invention,-   R4 is hydrogen or 1-4C-alkyl, and-   R5 is —O—R51, in which-   R51 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or    predominantly fluorine-substituted 1-4C-alkyl,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radical, in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, sulfanyl, cyano, 1-4C-alkoxycarbonyl, carboxyl,    hydroxyl, oxo, -A-N(R61)R62, pyridyl, or completely or partially    fluorine-substituted 1-4C-alkyl, in which-   A is a bond or 1-4C-alkylene,-   R61 is hydrogen or 1-4C-alkyl,-   R62 is hydrogen or 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which-   Het1 is optionally substituted by R611, and is a 3- to 7-membered    saturated or unsaturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one to three further heteroatoms independently selected    from the group consisting of oxygen, nitrogen and sulfur, in which-   R611 is 1-4C-alkyl,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, sulfanyl, hydroxyl, oxo, amino or mono- or    di-1-4C-alkylamino,-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

1-4C-Alkyl represents a straight-chain or branched alkyl radical having1 to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably theethyl and methyl radicals.

1-7C-Alkyl represents a straight-chain or branched alkyl radical having1 to 7 carbon atoms. Examples which may be mentioned are the heptyl,isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl(3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl(2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl,isopropyl, ethyl or methyl radicals.

1-4C-Alkylene is a straight chain alkylene radical having 1 to 4 carbonatoms. Examples which may be mentioned in this context are the methylene(—CH₂—), ethylene (—CH₂—CH₂—), trimethylene (—CH₂—CH₂—CH₂—) and thetetramethytene (—CH₂—CH₂—CH₂—CH₂—) radical.

1-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyand methoxy radicals.

2-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 2 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyradicals.

1-4C-Alkoxy-2-4C-alkoxy represents one of the abovementioned 2-4C-alkoxyradicals, which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the 2-methoxyethoxy, the2-ethoxyethoxy and the 2-isopropoxyethoxy radicals.

3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and cycle-heptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of whichcyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy arepreferred.

As completely or predominantly fluorine-substituted 1-4C-alkoxy, forexample, the 2,2,3,3,3-penta-fluoropropoxy, the perfluoroethoxy, the1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably thedifluoromethoxy radicals may be mentioned. “Predominantly” in thisconnection means that more than half of the hydrogen atoms of the1-4C-alkoxy radicals are replaced by fluorine atoms.

As completely or predominantly fluorine-substituted 1-4C-alkyl, forexample, the 2,2,3,3,3-pentafluoropropyl, the perfluoroethyl, the1,2,2-trifluoroethyl, in particular the 1,1,2,2-tetrafluoroethyl, the2,2,2-trifluoroethyl, the trifluoromethyl and particularly thedifluoromethyl radicals may be mentioned. “Predominantly” in thisconnection means that more than half of the hydrogen atoms of the1-4C-alkyl radicals are replaced by fluorine atoms.

As completely or partially fluorine-substituted 1-4C-alkyl, for example,the 2,2,3,3,3-pentafluoropropyl, the perfluoroethyl, the1,2,2-trifluoroethyl, the 1,1,2,2-tetrafluoroethyl, the2,2,2-trifluoroethyl, the trifluoromethyl, the difluoromethyl and, inparticular, the 2,2-difluoroethyl radicals may be mentioned.

1-2C-Alkylenedioxy represents, for example, the methylenedioxy[—O—CH₂—O] and the ethylenedioxy [—O—CH₂—CH₂—O—] radicals.

1-4C-Alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkylradicals, which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the methoxymethyl, themethoxyethyl and the isopropoxyethyl radicals, particularly the2-methoxyethyl and the 2-isopropoxyethyl radicals.

1-7C-Alkylcarbonyl represents a radical which, in addition to thecarbonyl group, contains one of the abovementioned 1-7C-alkyl radicals.Examples which may be mentioned are the acetyl, propionyl, butanoyl andhexanoyl radicals.

Hydroxy-2-4C-alkyl represents 2-4C-alkyl radicals, which are substitutedby a hydroxyl group. Examples which may be mentioned are the2-hydroxyethyl and the 3-hydroxypropyl radicals.

In addition to the nitrogen atom, mono- or di-1-4C-alkylamino radicalscontain one or two of the abovementioned 1-4C-alkyl radicals.Di-1-4C-alkylamino is preferred and here, in particular, dimethyl-,diethyl- or diisopropylamino.

Halogen within the meaning of the invention is bromine, chlorine orfluorine.

1-4C-Alkoxycarbonyl represents a radical which, in addition to thecarbonyl group, contains one of the abovementioned 1-4C-alkoxy radicals.Examples which may be mentioned are the methoxycarbonyl, theethoxycarbonyl and the isopropoxycarbonyl radicals.

1-4C-Alkylthio represents radicals which, in addition to the sulfuratom, contain one of the abovementioned 1-4C-alkyl radicals. Exampleswhich may be mentioned are the butylthio, propylthio and preferably theethylthio and methylthio radicals.

Pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl.

The term “oxo” as used herein refers to a doubly carbon-bonded oxygenatom, which form together with the carbon atom to which it is attached acarbonyl or keto group (C═O). An oxo group which is a substituent of a(hetero)aromatic ring results in a replacement of ═C(—H)— by —C(═O)— atits binding position. It will be apparent that the introduction of anoxo substituent on an (hetero)aromatic ring de-stroys the(hetero)aromaticity.

When A has the meaning “bond”, then the moiety —N(R61)R62 is directlyattached to the Har radical.

Har is optionally substituted by R6 and/or R7 and/or R8, and stands fora stabile 5- to 10-membered monocylic or fused bicyclic unsaturated(heteroaromatic) or partially saturated heteroaryl radical comprising 1to 4 heteroatoms selected independently from the group consisting ofoxygen, nitrogen and sulfur.

More precisely, Har is bonded to the tricyclic phenanthridine moiety viaa carbon ring atom, whereby all positional isomers are contemplated.

In an embodimental detail (detail 1a) according to this invention, Haris optionally substituted by R6 and/or R7, and is a 9- or 10-memberedbenzofused bicyclic partially saturated heteroaryl radical corn-prising1 to 2 heteroatoms selected independently from the group consisting ofoxygen, nitrogen and sulfur,

in particular in which

-   R6 is 1-4C-alkyl, completely or partially fluorine-substituted    1-4C-alkyl, or halogen, suitably fluorine,-   R7 is halogen, suitably fluorine.

In a sub-detail of detail 1a according to this invention, Har isoptionally substituted by R6 and/or R7, and is a 9- or 10-membered fusedbicyclic partially saturated heteroaryl radical comprising aheteroa-tom-free benzene ring and 1 or 2 heteroatoms selectedindependently from the group consisting of oxygen, nitrogen and sulfurin the other ring, in particular in which

-   R6 is 1-4C-alkyl, completely or partially fluorine-substituted    1-4C-alkyl, or halogen, suitably fluorine,-   R7 is halogen, suitably fluorine.

Har may include according to this detail 1a, without being restrictedthereto, indolinyl, isoindolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,benzo[1,3]dioxolyl, benzodioxanyl (i.e. dihydrobenzo[1,4]dioxinyl),dihydrobenzopyranyl, or dihydro-benzo[1,4]oxazinyl, as well as the R6-and/or R7-substituted derivatives thereof.

Illustratively, as exemplary suitable Har radicals according to detail1a may be mentioned, for example, without being restricted thereto,benzo[1,4]dioxanyl (i.e. dihydrobenzo[1,4]dioxinyl), benzo[1,3]dioxolylor 2,2-difluoro-benzo[1,3]dioxolyl.

As more specific exemplary suitable Har radicals according to detail 1amay be mentioned, for example, without being restricted thereto,benzo[1,4]dioxan-6-yl (i.e. dihydrobenzo[1,4]dioxin-6-yl),benzo[1,3]dioxol-5-yl or 2,2-difluoro-benzo[1,3]dioxol-5-yl.

In another embodimental detail (detail 1 b) according to this inventionHar is Cyc1, in which

-   Cyc1 is a partially aromatic group of formula Z

in which

-   G is optionally substituted by R6 and/or R7, and is a 5- or    6-membered saturated or partially unsaturated heterocyclic ring    comprising one or two heteroatoms independently selected from the    group consisting of nitrogen, oxygen and sulfur,    -   whereby said Cyc1 ring system is attached to the parent        molecular group via any substitutable carbon atom of the benzene        ring,        in which-   R6 is 1-4C-alkyl, completely or partially fluorine-substituted    1-4C-alkyl, or halogen such as e.g. fluorine,-   R7 is halogen such as e.g. fluorine.

As examples of Cyc1 according to detail 1b may be mentioned, withoutbeing restricted thereto, indolinyl, isoindolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothiophenyl, benzo[1,3]dioxolyl,dihydrobenzo[1,4]dioxinyl, chromanyl, chromenyl, ordihydrobenzo[1,4]oxazinyl, or 2,2-difluoro-benzo[1,3]dioxolyl, or4-methyl-3,4-dihydrobenzo[1,4]oxazinyl.

In yet another embodimental detail (detail 1c) according to thisinvention Har is Cyc1, in which Cyc1 is optionally substituted byhalogen, particularly chlorine, on its benzene ring, and is indolinyl,isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or3,4-dihydrobenzo[1,4]oxazinyl, or, particularly,

1-methyl-indolinyl, 2-methyl-isoindolinyl,1-methyl-tetrahydroquinolinyl, 2-methyl-tetrahydroisoquinolinyl, or4-methyl-3,4-dihydrobenzo[1,4]oxazinyl,

2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, benzo[1,3]dioxolyl,dihydrobenzo[1,4]dioxinyl, chromanyl, chromenyl, or2,2-difluoro-benzo[1,3]dioxolyl,

whereby said Cyc1 ring system is attached to the parent molecular groupvia any substitutable carbon atom of the benzene ring;

such as e.g. benzo[1,3]dioxol-5-yl, dihydrobenzo[1,4]dioxin-5-yl,2,2-difluoro-benzo[1,3]dioxol-5-yl, or5-chloro-4-methyl-3,4-dihydrobenzo[1,4]oxazin-7-yl.

In a further embodimental detail (detail 2a) according to thisinvention, Har is optionally substituted by R6, and is a 9- or10-membered fused bicyclic unsaturated (heteroaromatic) heteroarylradical comprising 1 to 4 heteroatoms independently selected from thegroup consisting of oxygen, nitrogen and sulfur,

in particular in which

-   R6 is 1-4C-alkyl, or completely or partially fluorine-substituted    1-4C-alkyl.

In a sub-detail of detail 2a according to this invention, Har isoptionally substituted by R6, and is a 9- or 10-membered fused bicyclicunsaturated (heteroaromatic) heteroaryl radical comprising aheteroa-tom-free benzene ring and 1 to 3 heteroatoms independentlyselected from the group consisting of oxygen, nitrogen and sulfur in theother ring,

in particular in which

-   R6 is 1-4C-alkyl, or completely or partially fluorine-substituted    1-4C-alkyl.

Har may include according to this detail 2a, without being restrictedthereto, the stabile benzo-fused derivatives of the Har radicalsmentioned in detail 3a or 3b below, such as e.g. benzothiophenyl,benzofuranyl, indolyl, benzoxazolyl, benzothiazolyl, indazolyl,benzimidazolyl, benzisoxazolyl, be nzisothi-azolyl, benzofurazanyl,benzotriazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, phthalazinyl or cinnolinyl; or indolizinyl,purinyl, naphthyridinyl or pteridinyl; as well as the R6-substitutedderivatives thereof.

Illustratively, as exemplary suitable Har radicals according to detail2a may be mentioned, for example, without being restricted thereto,quinolinyl, benzofurazanyl or benzothiazolyl.

As more specific exemplary suitable. Har radicals according to detail 2amay be mentioned, for example, without being restricted thereto,quinolin-6-yl, benzofurazanyl-5-yl or benzothiazol-6-yl.

In another further embodimental detail (detail 2b) according to thisinvention Har is Cyc2, in which Cyc2 is optionally substituted by R6and/or R7 and/or R8, and is a 9- or 10-membered fused bicyclic fullyaromatic ring system containing one to four heteroatoms each of which isselected from nitrogen, oxygen and sulphur, and which Cyc2 ring systemis made up of

-   -   a first constituent (constituent m) being a benzene ring, or a        6-membered monocyclic heteroaryl ring comprising one or two        nitrogen atoms (such as e.g. pyridine),        and fused to said first constituent m,    -   a second constituent (constituent n) being a 5- or 6-membered        monocytic heteroaryl ring comprising one to three heteroatoms        independently selected from the group consisting of nitrogen,        oxygen and sulphur.

In a particular embodiment, said Cyc2 ring system is attached to theparent molecular group via any substitutable ring carbon atom of theconstituent m.

In another embodiment, said Cyc2 ring system may be attached to theparent molecular group via any substitutable ring carbon atom of theconstituent n.

Har may include according to this detail 2b, without being restrictedthereto, the stabile benzo- or pyrido-fused derivatives of the Harradicals mentioned in detail 3a or 3b below, such as e.g. thebenzo-fused radicals benzothiophenyl, benzofuranyl, indolyl,benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, benzisoxazolyl,benzisothiazolyl, benzofurazanyl, benzotriazolyl, benzothiadiazolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,cinnolinyl, isoindolyl, isofuranyl or isobenzothiophenyl, or thepyrido-fused radicals pyrazolopyridinyl (such as e.g.pyrazolo[3,4-b]pyridinyl), pyrrolopyridinyl or imidazopyridinyl; as wellas indolizinyl, purinyl, naphthyridinyl or pteridinyl; and the R6-and/or R7- and/or R8-substituted derivatives thereof, in which R6, R7and R8 have the meanings as indicated in the description of thisinvention.

In more detailed example, Har may include according to this detail 2b,without being restricted thereto, quinolinyl, benzofurazanyl,benzothiazolyl, benzotriazolyl or pyrazolopyridinyl (such as e.g.pyre-zolo[3,4-b]pyridinyl); as well as the R6- and/or R7- and/orR8-substituted derivatives thereof, such as e.g.1-(1-4C-alkyl)-1H-benzotriazolyl or1-(1-4C-alkyl)-4-methoxy-3-methyl-1H-pyrazolo[3,4-b]pyridinyl.

Also in more detailed example, Har may include according to this detail2b, without being restricted thereto, benzothiazolyl, benzoxazolyl,benzimidazolyl, indazolyl, 1H-methyl-benzimidazolyl, or1-methyl-indazolyl, whereby these radicals may be attached to the parentmolecular group via the benzene ring.

Also in more detailed example, Har may include according to this detail2b, without being restricted thereto, benzoxadiazolyl (e.g.benzofurazanyl), benzotriazolyl, 1H-methyl-benzotriazolyl orbenzothiadiazolyl (e.g. benzo[1,2,3]thiadiazolyl), whereby theseradicals may be attached to the parent molecular group via the benzenering.

Also in more detailed example, Har may include according to this detail2b, without being restricted thereto, quinolinyl, isoquinolinyl,quinoxalinyl, quinazolinyl or cinnolinyl, whereby these radicals may beattached to the parent molecular group via the benzene ring.

Illustratively, as exemplary suitable Har radicals according to detail2b may be mentioned, for example, without being restricted thereto,quinolinyl, benzofurazanyl, benzothiazolyl,1-(1-4C-alkyl)-1H-benzotriazolyl or1-(1-4C-alkyl)-4-methoxy-3-methyl-1H-pyrazolo[3,4-b]pyridinyl, as wellas benzo[1,2,3]thiadiazolyl and quinoxalinyl.

As more specific exemplary suitable Har radicals according to detail 2bmay be mentioned, for example, without being restricted thereto,quinolin-6-yl, benzofurazan-5-yl, benzothiazol-6-yl,1-methyl-1H-benzotriazol-5-yl or4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl, as well asbenzo[1,2,3]thiadiazol-5-yl and quinoxalin-5-yl.

In a yet further embodimental detail (detail 3a) according to thisinvention, Har is optionally substituted by R6 and/or R7 and/or R8, andis a 5- or 6-membered monocyclic unsaturated (heteroaromatic) heteroarylradical comprising 1 to 4 heteroatoms selected independently from thegroup consisting of oxygen, nitrogen and sulfur,

in which

-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, cyano, 1-4C-alkoxycarbonyl, carboxyl, hydroxyl,    -A-N(R61)R62, pyridyl, or completely or partially    fluorine-substituted 1-4C-alkyl, in which-   A is a bond or 1-4C-alkylene,-   R61 is hydrogen or 1-4C-alkyl,-   R62 is hydrogen or 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which-   Het1 is optionally substituted by R611, and is a 3- to 7-membered    saturated or unsaturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one to three further heteroatoms independently selected    from the group consisting of oxygen, nitrogen and sulfur, in which-   R611 is 1-4C-alkyl,-   R7 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, 1-4C-alkylthio,    hydroxyl, amino or mono- or di-1-4C-alkylamino,-   R8 is halogen.

In another yet further embodimental detail (detail 3b) according to thisinvention, Har is optionally substituted by R6 and/or R7 and/or R8, andis a 5- or 6-membered monocyclic unsaturated (fully aromatic) heteroarylradical comprising 1 to 4 heteroatoms selected independently from thegroup consisting of oxygen, nitrogen and sulphur, in which R6, R7 and R8have the meanings as indicated in the description of this invention.

More precisely, in one embodiment of detail 3a or 3b according to thisinvention, Har is optionally substituted by R6 and/or R7 and/or R8, andis a 6-membered monocyclic unsaturated (heteroaromatic) heteroarylradical comprising 1 to 3, particularly 1 or 2, nitrogen atoms.

In addition, in another embodiment of detail 3a or 3b, Har is optionallysubstituted by R6 and/or R7, and is a 5-membered monocyclic unsaturated(heteroaromatic) heteroaryl radical comprising 1 to 4 heteroatomsselected independently from the group consisting of oxygen, nitrogen andsulfur.

Har may include according to detail 3a or 3b, without being restrictedthereto, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, triazolyl (precisely:1,2,4-triazolyl or 1,2,3-triazolyl), thiadiazolyl (precisely:1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or1,2,4-thiadiazolyl), oxadiazolyl (precisely: 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl) ortetrazolyl; or pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; as wellas the R6- and/or R7- and/or R8-substituted derivatives thereof.

In more detailed example, Har radicals according to detail 3a or 3b mayinclude, without being restricted thereto, isoxazolyl, imidazolyl,thiazolyl, oxazolyl, as well as the R6- and/or R7-substitutedderivatives thereof, or pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl, as well as the R6- and/or R7- and/or R8-substitutedderivatives thereof.

In still more detailed example, Har radicals according to detail 3a mayinclude, without being restricted thereto, pyridinyl, isoxazolyl,imidazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyrazinyl or pyridazinyl,as well as the R6- and/or R7-substituted derivatives thereof, wherein

-   R6 is 1-4C-alkyl, 1-4C-alkoxy, pyridyl or morpholin-4-yl,-   R7 is 1-4C-alkoxy.

In yet still more detailed embodimental example, Har radicals accordingto detail 3a may include, without being restricted thereto, isoxazolyl;N-(1-4C-alkyl)-imidazolyl; thiazolyl optionally substituted by pyridyl;or pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, each of which isoptionally substituted by R6- and/or R7 in which

-   R6 is 1-4C-alkoxy, mono- or di-1-4C-alkylamino, pyrazol-1-yl,    imidazol-1-yl, triazol-1-yl or morpholin-4-yl,-   R7 is 1-4C-alkoxy or mono- or di-1-4C-alkylamino,    such as, for example, 6-(morpholin-4-yl)-pyridin-3-yl, pyridin-3-yl,    pyridin-4-yl, 1-methyl-imidazol-2-yl, 2,6-dimethoxy-pyridin-4-yl,    2,6-dimethoxy-pyridin-3-yl, 3,6-dimethoxy-pyridazin-4-yl,    2,6-dimethoxy-pyrimidin-4-yl, 2,6-bis-dimethylamino-pyrimidin-4-yl,    pyrimidin-5-yl, pyrazin-2-yl, 6-(pyrazol-1-yl)-pyridin-3-yl,    6-(imidazol-1-yl)-pyridin-3-yl or    6-([1,2,4]triazol-1-yl)-pyridin-3-yl.

Illustratively, as exemplary suitable Har radicals according to detail3a may be mentioned, for example, without being restricted thereto,isoxazolyl; N-(1-4C-alkyl)-imidazolyl; thiazolyl optionally substitutedby pyridyl; or pyridinyl optionally substituted by R6- and/or R7 inwhich

-   R6 is 1-4C-alkoxy or morpholin-4-yl,-   R7 is 1-4C-alkoxy.

As more specific exemplary suitable Har radicals according to detail 3amay be mentioned, for example, without being restricted thereto,6-(morpholin-4-yl)-pyridin-3-yl, pyridin-3-yl, pyridin-4-yl,isoxazol-5-yl, 1-methyl-imidazol-2-yl, 1-methyl-imidazol-5-yl,2-(pyridin-3-yl)-thiazol-4-yl, or, in particular,2,6-dimethoxy-pyridin-4-yl or, in more particular,2,6-dimethoxy-pyridin-3-yl.

In still more detailed example, Har radicals according to detail 3b mayinclude, without being restricted thereto, pyridinyl, isoxazolyl,imidazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyrazinyl or pyridazinyl,as well as the R6- and/or R7- and/or R8-substituted derivatives thereof,wherein

-   R6 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, carboxyl,    pyridyl, piperidin-1-yl, morpholin-4-yl, pyrazol-1-yl or    imidazol-1-yl,-   R7 is 1-4C-alkoxy,-   R8 is halogen or 1-4C-alkoxy.

In yet still More detailed embodimental example, Har radicals accordingto detail 3b may include, without being restricted thereto,

-   isoxazolyl; N-(1-4C-alkyl)-imidazolyl;-   thiazolyl optionally substituted by pyridyl;-   pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, each of which is    optionally substituted by R6 and/or R7 and/or R8 in which    -   R6 is 1-4C-alkyl, 1-4C-alkoxy, pyrazol-1-yl, imidazol-1-yl,        piperidin-1-yl or morpholin-4-yl,    -   R7 is 1-4C-alkoxy,    -   R8 is 1-4C-alkoxy or halogen; or        pyridinyl, which is optionally substituted by R6 and/or R7        and/or R8 in which    -   R6 is 1-4C-alkoxy, pyrazol-1-yl, imidazol-1-yl, piperidin-1-yl,        morpholin-4-yl, 1-4C-alkoxycarbonyl or carboxyl,    -   R7 is 1-4C-alkoxy,    -   R8 is 1-4C-alkoxy or halogen.

As exemplary suitable Har radicals according to detail 3b may bementioned, for example, without being restricted thereto, pyridinyl,isoxazolyl, imidazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyrazinyl orpyridazinyl, each of which is optionally substituted by R6, in which

-   R6 is 1-4C-alkyl or pyridyl.

Yet as exemplary suitable Har radicals according to detail 3b may bementioned, for example, without being restricted thereto, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, each of which is optionallysubstituted by R6 and/or R7 and/or R8, in which

-   R6 is 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,-   R8 is 1-4C-alkoxy.

Yet as exemplary suitable Har radicals according to detail 3b may bementioned, for example, without being restricted thereto, pyridinyl,which is substituted by R6 and/or R7, in which

-   R6 is 1-4C-alkoxy,-   R7 is 1-4C-alkoxy.

Yet as exemplary suitable liar radicals according to detail 3b may bementioned, for example, without being restricted thereto, pyridinyl,which is substituted by R6 and/or R7 and R8, in which

-   R6 is 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,-   R8 is 1-4C-alkoxy or chlorine.

Yet as exemplary suitable Har radicals according to detail 3b may bementioned, for example, without Wing restricted thereto, pyrimidinyl,which is by R6 and/or R7 and/or R8, in which

-   R6 is 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,-   R8 is 1-4C-alkoxy.

Yet as exemplary suitable Har radicals according to detail 3b may bementioned, for example, without being restricted thereto, pyridinyl,which is substituted by R6, in which

-   R6 is 1-4C-alkoxycarbonyl or carboxyl.

Yet as exemplary suitable Har radicals according to detail 3b may bementioned, for example, without being restricted thereto, pyridinyl,which is substituted by R6, in which

-   R6 is morpholin-4-yl, piperidin-1-yl, pyrazol-1-yl or imidazol-1-yl.

As more specific exemplary suitable Har radicals according to detail 3bmay be mentioned, for example, without being restricted thereto,pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl,5-methyl-pyrazin-2-yl, isoxazol-5-yl, 1-methyl-imidazol-2-yl,1-methyl-imidazol-5-yl, 2-(pyridin-3-yl)-thiazol-4-yl,2,6-dimethoxy-pyridin-4-yl, 2,6-dimethoxy-pyridin-3-yl,2-methoxy-pyridin-3-yl, 6-(methoxycarbonyl)-pyridin-3-yl,5-(methoxycarbonyl)-pyridin-2-yl, 2,6-dimethoxypyrimidin-4-yl,2-methoxy-pyrimidin-5-yl, 2,4,6-trimethoxy-pyrimidin-5-yl,2,4-dimethoxy-pyrimidin-5-yl, 2,6-dimethoxy-pyrimidin-4-yl,6-(morpholin-4-yl)-pyridin-3-yl, 6-(piperidin-1-yl)-pyridin-3-yl,6-(pyrazol-1-yl)-pyridin-3-yl, 6-(imidazol-1-yl)-pyridin-3-yl, or3-chloro-2,6-dimethoxy-pyridin-4-yl.

In still more detailed example, Har radicals according to detail 3b mayalso include, without being restricted thereto, pyridinyl, isoxazolyl,imidazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyrazinyl or pyridazinyl,as well as the R6- and/or R7- and/or R8-substituted derivatives thereof,wherein

-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio,    1-4C-alkoxycarbonyl, carboxyl, hydroxyl, oxo, pyridyl or    -A-N(R61)R62, in which-   A is a bond or 1-4C-alkylene,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl,    thiomorpholin-4-yl, piperazin-1-yl or 4N-methyl-piperazin-1-yl,    or-   Het1 is pyrrol-1-yl, pyrazol-1-yl, triazol-1-yl or imidazol-1-yl,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, hydroxyl, oxo, or    di-1-4C-alkylamino,-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy.

In yet still more detailed embodimental example, Har radicals accordingto detail 3b may also include, without being restricted thereto,isoxazolyl, N-(1-4C-alkyl)-imidazolyl, and thiazolyl optionallysubstituted by pyridyl.

In yet still more detailed embodimental example, Har radicals accordingto detail 3b may also include, without being restricted thereto,

-   pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, each of which is    optionally substituted by R6 and/or R7 and/or R8 in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio,    1-4C-alkoxycarbonyl, carboxyl, hydroxyl, oxo, pyridyl or    -A-N(R61)R62, in which-   A is a bond or 1-2C-alkylene,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl or morpholin-4-yl,    or-   Het1 is pyrazol-1-yl or imidazol-1-yl,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, hydroxyl, oxo, or    di-1-4C-alkylamino,-   R8 is halogen or 1-4C-alkoxy.

As exemplary suitable Har radicals according to detail 3b may be alsomentioned, for example, without being restricted thereto, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, each of which is substituted byR6, in which

-   R6 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, 1-4C-alkoxycarbonyl,    carboxyl, hydroxyl, or -A-N(R61)R62, in which-   A is a bond, or 1-2C-alkylene,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl or morpholin-4-yl,    or-   Het1 is pyrazol-1-yl or imidazol-1-yl.

As exemplary suitable Har radicals according to detail 3b may be alsomentioned, for example, without being restricted thereto,

either

-   pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is    substituted by R6 and R7, in which-   R6 is halogen, 1-4C-alkoxy, 1-4C-alkylthio, oxo, or -A-N(R61)R62, in    which-   A is a bond,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl, and-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, or    di-1-4C-alkylamino,    or-   pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is    substituted by R6 and R8, in which-   R6 is -A-N(R61)R62, in which-   A is a bond,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl, and-   R8 is halogen.

As exemplary suitable Har radicals according to detail 3b may be alsomentioned, for example, without being restricted thereto,

-   pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is    substituted by R6 and R7 and R8, in    which-   R6 is 1-4C-alkoxy, or di-1-4C-alkylamino,-   R7 is 1-4C-alkoxy, or di-1-4C-alkylamino,-   R8 is halogen or 1-4C-alkoxy,

As exemplary suitable Har radicals according to detail 3b may be alsomentioned, for example, without being restricted thereto, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, each of which is unsubstituted.

As more detailed exemplary suitable Har radicals according to detail 3bmay be mentioned, for example, without being restricted thereto,pyridinyl which is substituted by R6, in which

-   R6 is 1-4C-alkoxy particularly 1-2C-alkoxy, 1-4C-alkylthio    particularly 1-2C-alkylthio, 1-4C-alkoxycarbonyl particularly    1-2C-alkoxycarbonyl, carboxyl, hydroxyl, or -A-N(R61)R62, in which-   A is a bond,-   R61 is 1-4C-alkyl, particularly 1-2C-alkyl,-   R62 is 1-4C-alkyl, particularly 1-2C-alkyl.

Yet as more detailed exemplary suitable Har radicals according to detail3b may be mentioned, for example, without being restricted thereto,pyridinyl which is substituted by R6, in which

-   R6 is -A-N(R61)R62, in which-   A is a bond, or 1-2C-alkylene, particularly ethylene,-   R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which-   Het1 is piperidin-1-yl, pyrrolidin-1-yl or morpholin-4-yl.

Yet as more detailed exemplary suitable Har radicals according to detail3b may be mentioned, for example, without being restricted thereto,pyridinyl which is substituted by R6, in which

-   R6 is -A-N(R61)R62, in which-   A is a bond,-   R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which-   Het1 is pyrrol-1-yl, triazol-1-yl, or, particularly, pyrazol-1-yl or    imidazol-1-yl.

Further, as more detailed exemplary suitable Har radicals according todetail 3b may be mentioned, for example, without being restrictedthereto, pyrimidinyl which is substituted by R6, in which

-   R6 is 1-4C-alkoxy, 1-4C-alkylthio, or -A-N(R61)R62, in which-   A is a bond,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl.

Further, as more detailed exemplary suitable Har radicals according todetail 3b may be mentioned, for example, without being restrictedthereto,

either

-   pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is    substituted by R6 and R7 in which-   R6 is 1-4C-alkoxy, and-   R7 is 1-4C-alkoxy,    or-   R6 is oxo, and-   R7 is 1-4C-alkyl,    or-   R6 is 1-4C-alkylthio, and-   R7 is 1-4C-alkyl,    or-   R6 is halogen, and-   R7 is 1-4C-alkylthio,    or-   R6 is di-1-4C-alkylamino, and-   R7 is 1-4C-alkoxy,    or-   R6 is di-1-4C-alkylamino, and-   R7 is di-1-4C-alkylamino;    or-   pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is    substituted by R6 and R8, in which-   R6 is di-1-4C-alkylamino, and-   R8 is halogen.

Further, as more detailed exemplary suitable Har radicals according todetail 3b may be mentioned, for example, without being restrictedthereto, pyridinyl, which is substituted by R6 and R7 in which

-   R6 is 1-4C-alkoxy, particularly 1-2C-alkoxy, and-   R7 is 1-4C-alkoxy, particularly 1-2C-alkoxy,

Yet as more detailed exemplary suitable Har radicals according to detail3b may be mentioned, for example, without being restricted thereto,pyridinyl, which is substituted by R6 and R7 in which

-   R6 is oxo, and-   R7 is 1-4C-alkyl, particularly 1-2C-alkyl,    such as, for example, N-(1-4C-alkyl)-pyridonyl, e.g.    N-(1-2C-alkyl)-pyrid-2-onyl.

Further, as more detailed exemplary suitable Har radicals according todetail 3b may be mentioned, for example, without being restrictedthereto,

either

-   pyrimidinyl, which is substituted by R6 and R7 in which-   R6 is 1-4C-alkoxy, particularly 1-2C-alkoxy, and-   R7 is 1-4C-alkoxy, particularly 1-2C-alkoxy,    or-   R6 is oxo, and-   R7 is 1-4C-alkyl, particularly 1-2C-alkyl,    or-   R6 is 1-4C-alkylthio, particularly 1-2C-alkylthio, and-   R7 is 1-4C-alkyl, particularly 1-2C-alkyl,    or-   R6 is halogen, particularly chlorine, and-   R7 is 1-4C-alkylthio, particularly 1-2C-alkylthio,    or-   R6 is di-1-4C-alkylamino, particularly di-1-2C-alkylamino, and-   R7 is 1-4C-alkoxy, particularly 1-2C-alkoxy,    or-   R6 is di-1-4C-alkylamino, particularly di-1-2C-alkylamino, and-   R7 is di-1-4C-alkylamino, particularly di-1-2C-alkylamino;    or-   pyrimidinyl, which is substituted by R6 and R8, in which-   R6 is di-1-4C-alkylamino, particularly di-1-2C-alkylamino, and-   R8 is halogen, particularly chlorine.

Further, as more detailed exemplary suitable Har radicals according todetail 3b may be mentioned, for example, without being restrictedthereto, pyridazinyl, which is substituted by R6 and R7 in which

-   R6 is 1-4C-alkoxy, particularly 1-2C-alkoxy, and-   R7 is 1-4C-alkoxy, particularly 1-2C-alkoxy.

Further, as more detailed exemplary suitable Har radicals according todetail 3b may be mentioned, for example, without being restrictedthereto, pyridin-3-yl, pyridin-4-yl, or pyrazin-2-yl, each of which isunsubstituted.

Yet as more detailed exemplary suitable Har radicals according to detail3b may be mentioned, for example, without being restricted thereto,pyrimidin-5-yl, which is unsubstituted.

Het1 is optionally substituted by R611 and stands for a stabilemonocylic 3- to 7-membered fully saturated or unsaturated(heteroaromatic) heterocyclic ring radical comprising the nitrogen atom,to which R61 and R62 are bonded, and optionally one to three furtherheteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulfur.

In a first facet (facet 1) according to this invention, Het1 isoptionally substituted by R611 on a ring nitrogen atom and stands for astabile monocylic 3- to 7-membered fully saturated heterocyclic ringradical comprising the nitrogen atom, to which R61 and R62 are bonded,and optionally one further heteroatom selected from the group consistingof nitrogen, oxygen and sulfur.

In a second facet (facet 2) according to this invention, Het1 stands fora stabile monocylic 5-membered unsaturated (heteroaromatic) ring radicalcomprising the nitrogen atom, to which R61 and R62 are bonded, andoptionally one to three further nitrogen atoms.

Het1 may include according to facet 1, without being restricted thereto,aziridinyl, azetidinyl, pyrrolid-inyl, piperidinyl, homopiperidinyl,morpholinyl, thiomorpholinyl, oxazolidinyl, isoxazolidinyl,thiazolid-inyl, isothiazolidinyl, pyrazolidinyl, imidazolidinyl,piperazinyl or homopiperazinyl.

Het1 may also include according to facet 2, without being restrictedthereto, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or tetrazolyl.

As further examples for Het1 according to this invention may bementioned, without being restricted thereto, R611-substitutedderivatives of the abovementioned exemplary Het1 radicals according tofacet 1, such as e.g. 4-N—(R611)-piperazinyl or4-N—(R611)-homopiperazinyl.

Illustratively, as exemplary suitable Het1 radicals according to facet 1may be mentioned, for example, without being restricted thereto,morpholin-4-yl, or piperidin-1-yl.

Illustratively, as exemplary suitable Het1 radicals according to facet 2may be mentioned, for example, without being restricted thereto,pyrazol-1-yl, or imidazol-1-yl.

In general, unless otherwise mentioned, the heterocyclic groupsmentioned herein refer to all of the possible isomeric forms thereof.

The heterocyclic groups mentioned herein refer, unless otherwise noted,in particular to all of the possible positional isomers thereof.

Thus, for example, the term pyridyl or pyridinyl includes pyridin-2-yl,pyridin-3-yl and pyridin-4-yl.

The heterocyclic groups mentioned herein refer, unless otherwise noted,yet in particular to all of the possible tautomers, e.g. the keto/enoltautomers, thereof, in pure form as well as any mixtures thereof.

Thus, for example, pyridine compounds which are substituted by ahydroxyl or an oxo group in the 2- or 4-position of the pyridine ringcan exist in different tautomeric forms, i.e. the enol and the ketoform, which are both contemplated by the present invention in pure formas well as in any mixtures thereof.

Constituents which are optionally substituted as stated herein, may besubstituted, unless otherwise noted, at any possible position.

The heterocyclic groups, alone or as part of other groups, mentionedherein may be substituted by their given substituents, unless otherwisenoted, at any possible position, such as e.g. at any substitutable ringcarbon or ring nitrogen atom.

Unless otherwise noted, rings containing quaternizable imino-type ringnitrogen atoms (—N═) may be preferably not quaternized on theseimino-type ring nitrogen atoms by the mentioned substituents; this maynot apply to compounds according to this invention which can escape fromthis quatemization by keto/enol tautomerism.

Unless otherwise noted, any heteroatom of a heterocyclic ring withunsatisfied valences mentioned herein is assumed to have the hydrogenatom(s) to satisfy the valences.

When any variable occurs more than one time in any constituent, eachdefinition is independent. As it is known for the person skilled in theart, compounds comprising nitrogen atoms can be form N-oxides.Particularly, imine nitrogen, especially heterocyclic or heteroaromaticimine nitrogen, or pyri-dine-type nitrogen (═N—) atoms, can beN-oxidized to form the N-oxides comprising the group ═N⁺(O⁻)—. Thus, thecompounds according to the present invention comprising the iminenitrogen atom in position 5 of the phenylphenanthridine backbone and,optionally (depending on the meaning of the substituents), one or morefurther nitrogen atoms suitable to exist in the N-oxide state (═N⁺(O⁻)—)may be capable to form (depending on the number of nitrogen atomssuitable to form stabile N-oxides) mono-N-oxides, bis-N-oxides ormulti-N-oxides, or mixtures thereof.

The term N-oxide(s) as used in this invention therefore encompasses allpossible, and in particular all stabile, N-oxide forms, such asmono-N-oxides, bis-N-oxides or multi-N-oxides, or mixtures thereof inany mixing ratio.

Possible salts for compounds of the formula I-depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerable saltsof the inorganic and organic acids and bases customarily used inpharmacy. Those suitable are, on the one hand, water-insoluble and,particularly, water-soluble acid addition salts with acids such as, forexample, hydrochloric acid, hydrobromic acid, phosphoric acid, nitricacid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoicacid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylicacid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, it beingpossible to employ the acids in salt preparation—depending on whether amono- or polybasic acid is con-cerned and depending on which salt isdesired—in an equimolar quantitative ratio or one differing therefrom.

In the context of the foregoing, as further acids, which may be used inthe preparation of possible salts of compounds of formula I, can bementioned adipic acid, L-ascorbic acid, L-aspartic acid,ben-zenesulfonic acid, 4-acetamido-benzoic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, caprylic acid (octanoic acid),dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, galactaric acid, gentisicacid, D-glucoheptonic acid, D-glucuronic acid, glutamic acid,2-oxo-glutaric acid, hippuric acid, lactic acid, malonic acid, mandelicacid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,nicotinic acid, palmitic acid, pamoic acid (embonic acid), andpyroglutamic acid.

On the other hand, salts with bases are also suitable. Examples of saltswith bases which may be mentioned are alkali metal (lithium, sodium,potassium) or calcium, aluminum, magnesium, titanium, ammonium,meglumine or guanidinium salts, where here too the bases are employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts which can initially be obtained, forexample, as process products in the preparation of the compoundsaccording to the invention on an industrial scale are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

It is known to the person skilled in the art that the compoundsaccording to the invention and their salts, when they are isolated, forexample, in crystalline form, can contain various amounts of solvents.The invention therefore also comprises all solvates and in particularall hydrates of the compounds of the formula I, and also all solvatesand in particular all hydrates of the salts of the compounds of theformula I.

Furthermore, the invention includes all conceivable tautomeric forms ofthe compounds of the present invention in pure form as well as anymixtures thereof. In this connection, the person skilled in the artknows that enolizable keto groups can exist, depending on the individualchemical surrounding, in their tautomeric enol forms, and vice versa. Asit is art-known hereby, keto and enol functions can mu-tually exchangein equilibrium. The invention includes in this context both the stableketo and the stable enol isomers of the compounds according to thisinvention in pure form, as well as the mixtures thereof, in any mixingratio.

Compounds of formula I according to aspect A more worthy to be mentionedin a sub-aspect (subaspect A1) are those, in which

-   R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen;    either, in a first embodiment (embodiment a) according to the    present invention,-   R4 is —O—R41, in which-   R41 is hydrogen or 1-4C-alkylcarbonyl, and-   R5 is hydrogen,    or, in a second embodiment (embodiment b) according to the present    invention,-   R4 is hydrogen, and-   R5 is —O—R51, in which-   R51 is hydrogen or 1-4C-alkylcarbonyl;    in one embodimental detail according to this invention,-   Har is Cyc1, in which-   Cyc1 is a group of formula Z

in which

-   G is optionally substituted by R6 and/or R7, and is a 5- or    6-membered saturated or partially unsaturated heterocyclic ring    comprising one or two heteroatoms independently selected from the    group consisting of nitrogen, oxygen and sulfur,    -   whereby said Cyc1 ring system is attached to the parent        molecular group via any substitutable carbon atom of the benzene        ring,        in which-   R6 is 1-2C-alkyl or halogen, such as e.g. fluorine,-   R7 is halogen, such as e.g. fluorine;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which-   Cyc2 is optionally substituted by R6 and/or R7 and/or R8, and is a    9- or 10-membered fused bicyclic fully aromatic ring system    containing one to four heteroatoms each of which is selected from    nitrogen, oxygen and sulphur, and which Cyc2 ring system is made up    of    -   a first constituent (constituent m) being a benzene ring, or a        6-membered monocyclic heteroaryl ring comprising one or two        nitrogen atoms,    -   and fused to said first constituent m,    -   a second constituent (constituent n) being a 5- or 6-membered        monocytic heteroaryl ring comprising one to three heteroatoms        independently selected from the group consisting of nitrogen,        oxygen and sulphur,    -   whereby said Cyc2 ring system is attached to the parent        molecular group via any substitutable ring carbon atom of the        constituent m,        in which-   R6 is 1-4C-alkyl or 1-4C-alkoxy,-   R7 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is 1-4C-alkyl or 1-4C-alkoxy;    or, in yet another embodimental detail according to this invention,    either-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    6-membered monocyclic unsaturated heteroarly radical comprising one    or two nitrogen atoms,    or-   Har is optionally substituted by R6 and/or R7, and is a 5-membered    monocyclic unsaturated heteroarly radical comprising one to four    heteroatoms selected independently from the group consisting of    oxygen, nitrogen and sulphur,    in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-ethoxy, cyano,    1-4C-alkoxycarbonyl, carboxyl, -A-N(R61)R62, or pyridyl, in which-   A is a bond or 1-2C-alkylene,-   R61 is hydrogen or 1-2C-alkyl,-   R62 is hydrogen or 1-2C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either, in one facet,-   Het1 is optionally substituted by R611 on a ring nitrogen atom, and    is a 5- to 7-membered saturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one further heteroatom selected from the group consisting    of oxygen, nitrogen and sulfur, in which-   R611 is 1-2C-alkyl,-   or, in another facet,-   Het1 is a 5-membered unsaturated monocyclic heteroaryl radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one to three further nitrogen atoms,-   R7 is 1-4C-alkyl, 1-4C-alkoxy-ethoxy or 1-4C-alkoxy,-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy,    and the salts, the N-oxides and the salts of the N-oxides of these    compounds.

Compounds of formula I according to aspect A in particular worthy to bementioned in a sub-aspect (subaspect A2) are those in which

-   R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen;-   R4 is —O—R41, in which-   R41 is 1-4C-alkylcarbonyl or hydrogen,-   R5 is hydrogen;

In one embodimental detail according to this invention,

-   Har is Cyc1, in which-   Cyc1 is a group of formula Z

in which

-   G is optionally substituted by R6 and/or R7, and is a 5- or    6-membered saturated or partially unsaturated heterocyclic ring    comprising one or two heteroatoms independently selected from the    group consisting of nitrogen, oxygen and sulfur,    -   whereby said Cyc1 ring system is attached to the parent        molecular group via any substitutable carbon atom of the benzene        ring,        in which-   R6 is halogen, such as e.g. fluorine,-   R7 is halogen, such as e.g. fluorine;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which-   Cyc2 is optionally substituted by R6 and/or R7 and/or R8, and is a    9- or 10-membered fused bicyclic fully aromatic ring system    containing one to four heteroatoms each of which is selected from    nitrogen, oxygen and sulphur, and which Cyc2 ring system is made up    of    -   a first constituent (constituent m) being a benzene or pyridine        ring, and fused to said first constituent m,    -   a second constituent (constituent n) being a 5- or 6-membered        monocylic heteroaryl ring comprising one to three heteroatoms        independently selected from the group consisting of nitrogen,        oxygen and sulphur,    -   whereby said Cyc2 ring system is attached to the parent        molecular group via any substitutable ring carbon atom of the        constituent m,        in which-   R6 is 1-4C-alkyl or 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,-   R8 is 1-4C-alkyl;    or, in yet another embodimental detail according to this invention,    either-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    6-membered monocyclic unsaturated heteroaryl radical comprising one    or two nitrogen atoms, such as e.g. pyridinyl, pyrimidinyl or    pyrazinyl,    in which-   R6 is 1-4C-alkyl, 1-4C-alkoxy, cyano, 1-4C-alkoxycarbonyl, carboxyl,    or -A-N(R61)R62, in which-   A is a bond,-   R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either, in one facet,-   Het1 is optionally substituted by R611 on a ring nitrogen atom, and    is a 5- to 7-membered saturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one further heteroatom selected from the group consisting    of oxygen, nitrogen and sulfur, such as e.g. piperidin-1-yl or    morpholin-4-yl, in which-   R611 is 1-2C-alkyl,    or, in another facet,-   Het1 is a 5-membered unsaturated monocyclic heteroaryl radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one to three further nitrogen atoms, such as e.g.    imidazol-1-yl or pyrazol-1-yl,-   R7 is 1-4C-alkoxy,-   R8 is halogen or 1-4C-alkoxy;    or-   Har is optionally substituted by R6 and/or R7, and is a 5-membered    monocyclic unsaturated heteroaryl radical comprising one to four    heteroatoms selected independently from from the group consisting of    oxygen, nitrogen and sulphur,    -   such as e.g. isoxazolyl, oxazolyl, imidazolyl or thiazolyl,        in which-   R6 is 1-4C-alkyl or pyridyl-   R7 is 1-4C-alkyl;    and the salts, the N-oxides and the salts of the N-oxides of these    compounds.

Compounds of formula I according to aspect A in more particular worthyto be mentioned in a sub-aspect (subaspect A3) are those in which

-   R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen;-   R4 is —O—R41, in which-   R41 is 1-4C-alkylcarbonyl such as e.g. acetyl, or, particularly,    hydrogen,-   R5 is hydrogen;    in one embodimental detail according to this invention,-   Har is Cyc1, in which-   Cyc1 is dihydrobenzo[1,4]dioxinyl, benzo[1,3]dioxolyl or    2,2-difluoro-benzo[1,3]dioxolyl;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which-   Cyc2 is optionally substituted by R6 and/or R7, and is quinolinyl,    benzofurazanyl, benzothiazolyl, 1-(1-4C-alkyl)-1H-benzotriazolyl or    1-(1-4C-alkyl)-1H-pyrazolo[3,4-b]pyridinyl, in which-   R6 is 1-4C-alkyl or 1-4C-alkoxy,-   R7 is 1-4C-alkoxy;    or, in yet another embodimental detail according to this invention,    either-   Har is optionally substituted by R6, and is pyridinyl, pyrimidinyl,    pyrazinyl, isoxazolyl, 1-(1-4C-alkyl)-1H-imidazolyl or thiazolyl, in    which-   R6 is 1-4C-alkyl or pyridyl,    or-   Har is substituted by R6 and/or R7 and/or R8, and is pyrimidinyl, in    which-   R6 is 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,-   R8 is 1-4C-alkoxy,    or-   Har is substituted by R6 and/or R7 and/or R8, and is pyridinyl, in    which-   R6 is 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R7 is 1-4C-alkoxy,-   R8 is 1-4C-alkoxy or halogen,    or-   Har is substituted by R6, and is pyridinyl, in which-   R6 is morpholin-4-yl, piperidin-1-yl, pyrazol-1-yl or imidazol-1-yl;    and the salts, the N-oxides and the salts of the N-oxides of these    compounds.

Compounds of formula I according to aspect A in still more particularworthy to be mentioned in a sub-aspect (subaspect A4) are those in which

-   R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen;-   R4 is —O—R41, in which-   R41 is hydrogen-   R5 is hydrogen;    in one embodimental detail according to this invention,-   Har is Cyc1, in which-   Cyc1 is dihydrobenzo[1,4]dioxinyl, benzo[1,3]dioxolyl or    2,2-difluoro-benzo[1,3]dioxolyl, such as e.g.    dihydrobenzo[1,4]dioxin-6-yl, benzo[1,3]dioxol-5-yl, or    2,2-difluoro-benzo[1,3]dioxol-5-yl;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which    either-   Cyc2 is quinolinyl, benzofurazanyl or benzothiazolyl,    -   such as e.g. quinolin-6-yl, benzofurazan-5-yl or        benzothiazol-6-yl,        or-   Cyc2 is 1-(1-4C-alkyl)-1H-benzotriazolyl or    1-(1-4C-alkyl)-4-methoxy-3-methyl-1H-pyrazolo[3,4-b]pyridinyl,    -   such as e.g. 1-methyl-1H-benzotriazol-5-yl or        4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl;        or, in yet another embodimental detail according to this        invention,        either-   Har is pyridinyl, pyrimidinyl, isoxazolyl,    1-(1-4C-alkyl)-1H-imidazolyl, methyl-pyrazinyl or pyridyl-thiazolyl,    -   such as e.g. pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl,        pyrazin-2-yl, 5-methyl-pyrazin-2-yl, isoxazol-5-yl,        1-methyl-imidazol-2-yl, 1-methyl-imidazol-5-yl or        2-(pyridin-3-yl)-thiazol-4-yl,        or-   Har is substituted by R6 and/or R7 and/or R8, and is pyrimidinyl, in    which-   R6 is 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,-   R8 is 1-4C-alkoxy,    -   such as e.g. 2,6-dimethoxypyrimidin-4-yl,        2-methoxy-pyrimidin-5-yl, 2,4,6-trimethoxy-pyrimidin-5-yl,        2,4-dimethoxy-pyrimidin-5-yl or 2,6-dimethoxy-pyrimidin-4-yl,        or-   Har is substituted by R6, and is pyridinyl, in which-   R6 is 1-4C-alkoxycarbonyl,    -   such as e.g. 6-(methoxycarbonyl)-pyridin-3-yl or        5-(methoxycarbonyl)-pyridin-2-yl,        or-   Har is substituted by R6, and is pyridinyl, in which-   R6 is morpholin-4-yl, piperidin-1-yl, pyrazol-1-yl or imidazol-1-yl,    such as e.g. 6-(morpholin-4-yl)-pyridin-3-yl,    6-(piperidin-1-yl)-pyridin-3-yl, 6-(pyrazol-1-yl)-pyridin-3-yl or    6-(imidazol-1-yl)-pyridin-3-yl,    or-   Har is substituted by R6 and/or R7, and is pyridinyl, in which-   R6 is 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,    -   such as e.g. 2,6-dimethoxy-pyridin-4-yl,        2,6-dimethoxy-pyridin-3-yl or 2-methoxy-pyridin-3-yl,        or-   Har is substituted by R6 and R7 and R8, and is pyridinyl, in which-   R6 is 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,-   R8 is chlorine,    -   such as e.g. 3-chloro-2,6-dimethoxy-pyridin-4-yl;        and the salts, the N-oxides and the salts of the N-oxides of        these compounds.

Yet compounds of formula I according to aspect A more worthy to bementioned in a sub-aspect (sub-aspect A1′) are those, in which

-   R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen;    either, in a first embodiment (embodiment a) according to the    present invention,-   R4 is —O—R41, in which-   R41 is hydrogen or 1-4C-alkylcarbonyl, and-   R5 is hydrogen,    or, in a second embodiment (embodiment b) according to the present    invention,-   R4 is hydrogen, and-   R5 is —O—R51, in which-   R51 is hydrogen or 1-4C-alkylcarbonyl;    in one embodimental detail according to this invention,-   Har is optionally substituted by R6 and/or R7, and is a 9- or    10-membered fused bicyclic partially saturated heteroaryl radical    comprising a heteroatom-free benzene ring and, in the other ring, 1    or 2 heteroatoms independently selected from oxygen, nitrogen and    sulfur,    -   whereby said Har ring system is attached to the parent molecular        group via any substitutable carbon atom of the benzene ring,        in which-   R6 is 1-4C-alkyl or halogen,-   R7 is halogen;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which-   Cyc2 is optionally substituted by R6 and/or R7 and/or R8, and is a    9- or 10-membered fused bicyclic fully aromatic ring system    containing one to four heteroatoms each of which is selected from    nitrogen, oxygen and sulphur, and which Cyc2 ring system is made up    of    -   a first constituent (constituent m) being a benzene or pyridine        ring,    -   and fused to said first constituent m,    -   a second constituent (constituent n) being a 5- or 6-membered        monocylic heteroaryl ring comprising one to three heteroatoms        independently selected from the group consisting of nitrogen,        oxygen and sulphur,    -   whereby said Cyc2 ring system is attached to the parent        molecular group via any substitutable ring carbon atom of the        constituent m,        in which-   R6 is 1-4C-alkyl or 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,-   R8 is 1-4C-alkyl;    or, in yet another embodimental detail according to this invention,    either-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    6-membered monocyclic unsaturated heteroarly radical comprising one    or two nitrogen atoms,    or-   Har is optionally substituted by R6 and/or R7, and is a 5-membered    monocyclic unsaturated heteroarly radical comprising one to four    heteroatoms selected independently from the group consisting of    oxygen, nitrogen and sulphur,    in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, sulfanyl, cyano, 1-4C-alkoxycarbonyl, carboxyl,    hydroxyl, oxo, -A-N(R61)R62, or pyridyl, in which-   A is a bond or 1-4C-alkylene,-   R61 is hydrogen or 1-4C-alkyl,-   R62 is hydrogen or 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either, in one facet,-   Het1 is optionally substituted by R611 on a ring nitrogen atom, and    is a 5- to 7-membered saturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one further heteroatom selected from the group consisting    of oxygen, nitrogen and sulfur, in which-   R611 is 1-4C-alkyl,    or, in another facet,-   Het1 is a 5-membered unsaturated monocyclic heteroaryl radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one to three further nitrogen atoms,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, sulfanyl, hydroxyl, oxo, amino, or mono- or    di-1-4C-alkylamino,-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Yet compounds of formula I according to aspect A in particular worthy tobe mentioned in a sub-aspect (subaspect A2′) are those, in which

-   R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen;    either, in a first embodiment (embodiment a) according to the    present invention,-   R4 is —O—R41, in which-   R41 is hydrogen or 1-4C-alkylcarbonyl, and-   R5 is hydrogen,    or, in a second embodiment (embodiment b) according to the present    invention,-   R4 is hydrogen, and-   R5 is —O—R51, in which-   R51 is hydrogen or 1-4C-alkylcarbonyl;    in one embodimental detail according to this invention,-   Har is Cyc1, in which-   Cyc1 is optionally substituted by halogen on its benzene ring, and    is indolinyl, isoindolinyl, tetrahydroquinolinyl,    tetrahydroisoquinolinyl, 3,4-dihydrobenzo[1,4]oxazinyl,    1-methyl-indolinyl, 2-methyl-isoindolinyl,    1-methyl-tetrahydroquinolinyl, 2-methyl-tetrahydroisoquinolinyl,    4-methyl-3,4-dihydrobenzo[1,4]oxazinyl, 2,3-dihydrobenzofuranyl,    2,3-dihydrobenzothiophenyl, benzo[1,3]dioxolyl,    dihydro-benzo[1,4]dioxinyl, chromanyl, chromenyl, or    2,2-difluoro-benzo[1,3]dioxolyl,    whereby said Cyc1 ring system is attached to the parent molecular    group via any substitutable carbon atom of the benzene ring;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which-   Cyc2 is optionally substituted by R6 and/or R7 and/or R8, and is a    9- or 10-membered fused bicyclic fully aromatic ring system    containing one to three heteroatoms each of which is selected from    nitrogen, oxygen and sulphur, and which Cyc2 ring system is made up    of    -   a first constituent (constituent m) being a benzene or pyridine        ring,    -   and fused to said first constituent m,    -   a second constituent (constituent n) being a 5- or 6-membered        monocytic heteroaryl ring comprising one to three heteroatoms        independently selected from the group consisting of nitrogen,        oxygen and sulphur,    -   whereby said Cyc2 ring system is attached to the parent        molecular group via any substitutable ring carbon atom of the        constituent m,        in which-   R6 is 1-4C-alkyl or 1-4C-alkoxy,-   R7 is 1-4C-alkoxy,-   R8 is 1-4C-alkyl;    or, in yet another embodimental detail according to this invention,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radical, in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio,    1-4C-alkoxycarbonyl, carboxyl, hydroxyl, oxo, or -A-N(R61)R62, in    which-   A is a bond or 1-4C-alkylene,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl,    thiomorpholin-4-yl, piperazin-1-yl or 4N-methyl-piperazin-1-yl,    or-   Het1 is pyrrol-1-yl, pyrazol-1-yl, triazol-1-yl or imidazol-1-yl,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, hydroxyl, oxo, or    di-1-4C-alkylamino,-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy;    or, in still yet another embodimental detail according to this    invention,-   Har is optionally substituted by R6 and/or R7, and is a 5-membered    monocyclic unsaturated heteroarly radical comprising one to four    heteroatoms selected independently from the group consisting of    oxygen, nitrogen and sulphur,    in which-   R6 is 1-4C-alkyl, or pyridyl,-   R7 is 1-4C-alkyl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Yet compounds of formula I according to aspect A in more particularworthy to be mentioned in a sub-aspect (subaspect A3′) are those, inwhich

-   one of R1 and R2 is methoxy or ethoxy, and the other is methoxy,    ethoxy, 2,2-difluoroethoxy or difluoromethoxy,-   R3 is hydrogen,-   R31 is hydrogen;-   R4 is —O—R41, in which-   R41 is hydrogen or 1-4C-alkylcarbonyl, and-   R5 is hydrogen,    in one embodimental detail according to this invention,-   Har is Cyc1, in which-   Cyc1 is optionally substituted by chlorine on its benzene ring, and    is indolinyl, isoindolinyl, tetrahydroquinolinyl,    tetrahydroisoquinolinyl, or 3,4-dihydrobenzo[1,4]oxazinyl,    1-methyl-indolinyl, 2-methyl-isoindolinyl,    1-methyl-tetrahydroquinolinyl, 2-methyl-tetrahydroisoquinolinyl, or    4-methyl-3,4-dihydrobenzo[1,4]oxazinyl, 2,3-dihydrobenzofuranyl,    2,3-dihydrobenzothiophenyl, benzo[1,3]dioxolyl,    dihydro-benzo[1,4]dioxinyl, chromanyl, chromenyl, or    2,2-difluoro-benzo[1,3]dioxolyl,    whereby said Cyc1 ring system is attached to the parent molecular    group via any substitutable carbon atom of the benzene ring;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which-   Cyc2 is optionally substituted by R6 and/or R7, and is    -   either    -   pyrazolopyridinyl or 1-methyl-pyrazolopyridinyl,-   whereby these radicals may be attached to the parent molecular group    via the pyridine ring,    -   or    -   benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl,        1-methyl-benzimidazolyl, 1-methyl-indazolyl, benzoxadiazolyl,        benzotriazolyl, 1H-methyl-benzotriazolyl, benzothiadiazolyl,        quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl or        cinnolinyl,        whereby these radicals may be attached to the parent molecular        group via the benzene ring,        in which-   R6 is 1-4C-alkyl or 1-4C-alkoxy,-   R7 is 1-4C-alkoxy;    or, in yet another embodimental detail according to this invention,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radical, in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio,    1-4C-alkoxycarbonyl, carboxyl, hydroxyl, oxo, or -A-N(R61)R62, in    which-   A is a bond or 1-4C-alkylene,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl,    thiomorpholin-4-yl, piperazin-1-yl or 4N-methyl-piperazin-1-yl,    or-   Het1 is pyrrol-1-yl, pyrazol-1-yl, triazol-1-yl or imidazol-1-yl,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, hydroxyl, oxo, or    di-1-4C-alkylamino,-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy;    or, in still yet another embodimental detail according to this    invention,-   Har is optionally substituted by R6 and/or R7, and is a 5-membered    monocyclic unsaturated heteroarly radical comprising one to four    heteroatoms selected independently from the group consisting of    oxygen, nitrogen and sulphur,    in which-   R6 is 1-4C-alkyl, or pyridyl,-   R7 is 1-4C-alkyl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Yet compounds of formula I according to aspect A in still moreparticular worthy to be mentioned in a sub-aspect (subaspect A4′) arethose, in which

-   R1 is methoxy or ethoxy,-   R2 is methoxy, ethoxy, 2,2-difluoroethoxy or difluoromethoxy,-   R3 is hydrogen,-   R31 is hydrogen;-   R4 is —O—R41, in which-   R41 is hydrogen or acetyl, and-   R5 is hydrogen,    in one embodimental detail according to this invention,-   Har is Cyc1, in which-   Cyc1 is benzo[1,3]dioxol-5-yl, dihydrobenzo[1,4]dioxin-5-yl,    2,2-difluoro-benzo[1,3]dioxol-5-yl, or    5-chloro-4-methyl-3,4-dihydrobenzo[1,4]oxazin-7-yl;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which-   Cyc2 is quinolin-6-yl, benzofurazan-5-yl, benzothiazol-6-yl,    1-methyl-1H-benzotriazol-5-yl or    4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl,    benzo[1,2,3]thiadiazol-5-yl or quinoxalin-5-yl;    or, in yet another embodimental detail according to this invention,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radical, in which-   R6 is chlorine, methyl, methoxy, ethoxy, methylthio,    methoxycarbonyl, carboxyl, hydroxyl, oxo, or -A-N(R61)R62, in which-   A is a bond or ethylene,-   R61 is methyl,-   R62 is methyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl or morpholin-4-yl,    or-   Het1 is pyrazol-1-yl or imidazol-1-yl,-   R7 is methyl, methoxy, ethoxy, methylthio or dimethylamino,-   R8 is chlorine or methoxy;    or, in still yet another embodimental detail according to this    invention,-   Har is isoxazolyl, 1-methylimidazolyl, or pyridyl-thiazolyl;    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Particular compounds of formula I according to aspect A to be mentionedin a sub-aspect (subaspect A5) are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, 2,2-difluoroethoxy or difluoromethoxy,-   R3 is hydrogen,-   R31 is hydrogen;-   R4 is —O—R41, in which-   R41 is hydrogen or acetyl, and-   R5 is hydrogen,    in one embodimental detail according to this invention,-   Har is Cyc1, in which-   Cyc1 is benzo[1,3]dioxol-5-yl, dihydrobenzo[1,4]dioxin-5-yl,    2,2-difluoro-benzo[1,3]dioxol-5-yl, or 5-chloro-4-methyl-3,4-di    hydrobenzo[1,4]oxazin-7-yl;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which-   Cyc2 is quinolin-6-yl, benzofurazan-5-yl, benzothiazol-6-yl,    1-methyl-1H-benzotriazol-5-yl or    4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl,    benzo[1,2,3]thiadiazol-5-yl or quinoxalin-5-yl;    or, in yet another embodimental detail according to this invention,-   Har is pyridin-3-yl, pyridin-4-yl, 6-(piperidin-1-yl)-pyridin-3-yl,    6-(pyrazol-1-yl)-pyridin-3-yl, 6-(imidazol-1-yl)-pyridin-3-yl,    6-methoxycarbonyl-pyridin-3-yl, 3-methoxycarbonyl-pyridin-2-yl,    2-methoxy-pyridin-3-yl, 6-methoxy-pyridin-3-yl,    2-methylsulfanyl-pyridin-3-yl, 6-hydroxy-pyridin-3-yl,    6-carboxy-pyridin-3-yl, pyrimidin-5-yl, 2-methoxy-pyrimidin-5-yl,    2-dimethylamino-pyrimidin-5-yl, 2-methylsulfanyl-pyrimidin-5-yl,    pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 2,6-dimethoxy-pyridin-3-yl,    2,6-dimethoxy-pyridin-4-yl, 4,6-dimethoxy-pyridin-3-yl,    5,6-dimethoxy-pyridin-3-yl, 4,6-diethoxy-pyridin-3-yl,    5-ethoxy-6-methoxy-pyridin-3-yl, 1-methyl-1H-pyridin-2-one-5-yl,    2,6-dimethoxy-pyrimidin-4-yl, 2,4-dimethoxy-pyrimidin-5-yl, 4,6-di    methoxy-pyrimidin-5-yl, 4-methyl-2-methylsulfanyl-pyrimidin-5-yl,    5-chloro-2-methylsulfanyl-pyrimidin-4-yl,    4-chloro-2-dimethylamino-pyrimidin-5-yl,    2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl, 3,6-dimethoxy-pyridazin-4-yl,    4-chloro-2,6-dimethoxy-pyridin-3-yl,    3-chloro-2,6-dimethoxy-pyridin-4-yl,    5-chloro-2,6-bisdimethylamino-pyrimidin-4-yl, or    2,4,6-trimethoxy-pyrimidin-5-yl;    or, in still yet another embodimental detail according to this    invention,-   Har is isoxazol-5-yl, 1-methylimidazol-2-yl, 1-methylimidazol-5-yl,    or 2-(pyridin-3-yl)-thiazol-4-yl; and the enantiomers, as well as    the salts, the N-oxides and the salts of the N-oxides of these    compounds and enantiomers.

More particular compounds of formula I according to aspect A to bementioned in a sub-aspect (sub-aspect A6) are those, in which

-   R1 is methoxy,-   R2 is ethoxy, 2,2-difluoroethoxy or difluoromethoxy,-   R3 is hydrogen,-   R31 is hydrogen;-   R4 is —O—R41, in which-   R41 is hydrogen, and-   R5 is hydrogen,    in one embodimental detail according to this invention,-   Har is Cyc1, in which-   Cyc1 is benzo[1,3]dioxol-5-yl, dihydrobenzo[1,4]dioxin-5-yl,    2,2-difluoro-benzo[1,3]dioxol-5-yl, or    5-chloro-4-methyl-3,4-dihydrobenzo[1,4]oxazin-7-yl;    or, in another embodimental detail according to this invention,-   Har is Cyc2, in which-   Cyc2 is quinolin-6-yl, benzofurazan-5-yl, benzothiazol-6-yl,    1-methyl-1H-benzotriazol-5-yl or    4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl,    benzo[1,2,3]thiadiazol-5-yl or quinoxalin-5-yl;    or, in yet another embodimental detail according to this invention,-   Har is pyridin-3-yl, pyridin-4-yl, 6-(morpholin-4-yl)-pyridin-3-yl,    6-(piperidin-1-yl)-pyridin-3-yl, 6-(pyrazol-1-yl)-pyridin-3-yl,    6-(imidazol-1-yl)-pyridin-3-yl, 6-methoxycarbonyl-pyridin-3-yl,    3-methoxycarbonyl-pyridin-2-yl, 2-methoxy-pyridin-3-yl,    6-methoxy-pyridin-3-yl, 2-methylsulfanyl-pyridin-3-yl,    6-hydroxy-pyridin-3-yl, 6-carboxy-pyridin-3-yl, pyrimidin-5-yl,    2-methoxy-pyrimidin-5-yl, 2-dimethylamino-pyrimidin-5-yl,    2-methylsulfanyl-pyrimidin-5-yl, pyrazin-2-yl,    5-methyl-pyrazin-2-yl, 6-[2-(pyrrolidin-1-yl)-ethyl]-pyridin-3-yl,    2,6-dimethoxy-pyridin-3-yl, 2,6-dimethoxy-pyridin-4-yl,    4,6-dimethoxy-pyridin-3-yl, 5,6-dimethoxy-pyridin-3-yl,    4,6-diethoxy-pyridin-3-yl, 5-ethoxy-6-methoxy-pyridin-3-yl,    1-methyl-1H-pyridin-2-one-5-yl, 2,6-dimethoxy-pyrimidin-4-yl,    2,4-dimethoxy-pyrimidin-5-yl, 4,6-dimethoxy-pyrimidin-5-yl,    4-methyl-2-methylsulfanyl-pyrimidin-5-yl,    5-chloro-2-methylsulfanyl-pyrimidin-4-yl,    4-chloro-2-dimethylamino-pyrimidin-5-yl,    2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl, 3,6-dimethoxy-pyridazin-4-yl,    4-chloro-2,6-dimethoxy-pyridin-3-yl,    3-chloro-2,6-dimethoxy-pyridin-4-yl,    5-chloro-2,6-bisdimethylamino-pyrimidin-4-yl, or    2,4,6-trimethoxy-pyrimidin-5-yl;    or, in still yet another embodimental detail according to this    invention,-   Har is isoxazol-5-yl, 1-methylimidazol-2-yl, 1-methylimidazol-5-yl,    or 2-(pyridin-3-yl)-thiazol-4-yl;    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect B more worthy to be mentionedin a sub-aspect (subaspect B1) are those in which

-   R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen,    either, in a first embodiment (embodiment a) according to the    present invention,-   R4 is —O—R41, in which-   R41 is hydrogen or 1-4C-alkylcarbonyl, and-   R5 is hydrogen,    or, in a second embodiment (embodiment b) according to the present    invention,-   R4 is hydrogen, and-   R5 is —O—R51, in which-   R51 is hydrogen or 1-4C-alkylcarbonyl,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is    -   a 9- or 10-membered benzofused bicyclic partially saturated        heteroaryl radical comprising 1 or 2 heteroatoms selected        independently from the group consisting of oxygen, nitrogen and        sulfur,        or    -   a 9- or 10-membered fused bicyclic unsaturated heteroaryl        radical comprising 1 to 4 heteroatoms selected independently        from the group consisting of oxygen, nitrogen and sulfur,        or    -   a 5- or 6-membered monocyclic unsaturated heteroaryl radical        comprising 1 to 4 heteroatoms selected independently from the        group consisting of oxygen, nitrogen and sulfur,        in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, cyano, 1-4C-alkoxycarbonyl, carboxyl, hydroxyl,    -A-N(R61)R62, pyridyl, or completely or partially    fluorine-substituted 1-4C-alkyl, in which-   A is a bond or 1-4C-alkylene,-   R61 is hydrogen or 1-4C-alkyl,-   R62 is hydrogen or 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either, in one facet,-   Het1 is optionally substituted by R611 on a ring nitrogen atom, and    is a 3- to 7-membered saturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one further heteroatom selected from the group consisting    of oxygen, nitrogen and sulfur, in which-   R611 is 1-4C-alkyl,    or, in another facet,-   Het1 is a 5-membered unsaturated monocyclic heterocyclic ring    radical comprising the nitrogen atom, to which R61 and R62 are    bonded, and optionally one to three further nitrogen atoms,-   R7 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, 1-4C-alkylthio,    hydroxyl, amino or mono- or di-1-4C-alkylamino,-   R8 is halogen,    and the salts, the N-oxides and the salts of the N-oxides of these    compounds.

Compounds of formula I according to aspect B in particular worthy to bementioned in a sub-aspect (subaspect B2) are those in which

-   R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is 1-4C-alkylcarbonyl or, in particular, in an individual    embodiment according to this invention, hydrogen,-   R5 is hydrogen,    in one embodimental detail according to this invention,-   Har is optionally substituted by R6 and/or R7, and is a 9- or    10-membered benzofused bicyclic partially saturated heteroaryl    radical comprising 1 or 2 heteroatoms selected independently from    the group consisting of oxygen, nitrogen and sulfur, in which-   R6 is 1-2C-alkyl or halogen,-   R7 is halogen;    or, in another embodimental detail according to this invention,-   Har is optionally substituted by R6, and is a 9- or 10-membered    fused bicyclic unsaturated heteroaryl radical comprising 1 to 3    heteroatoms selected independently from the group consisting of    oxygen, nitrogen and sulfur, in which-   R6 is 1-4C-alkyl;    or, in yet another embodimental detail according to this invention,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a 5-    or 6-membered monocyclic unsaturated heteroaryl radical comprising 1    to 3 heteroatoms selected independently from the group consisting of    oxygen, nitrogen and sulfur, in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-ethoxy,    1-2C-alkylthio, cyano, 1-2C-alkoxycarbonyl, carboxyl, hydroxyl,    -A-N(R61)R62, pyridyl, or completely or partially    fluorine-substituted 1-2C-alkyl, in which-   A is a bond or 1-2C-alkylene,-   R61 is hydrogen or 1-2C-alkyl,-   R62 is hydrogen or 1-2C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either, in one facet,-   Het1 is optionally substituted by R611 on a ring nitrogen atom, and    is a 5- to 7-membered saturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one further heteroatom selected from the group consisting    of oxygen, nitrogen and sulfur, in which-   R611 is 1-2C-alkyl,    or, in another facet,-   Het1 is a 5-membered unsaturated monocyclic heterocyclic ring    radical comprising the nitrogen atom, to which R61 and R62 are    bonded, and optionally one or two further nitrogen atoms,-   R7 is 1-4C-alkoxy, 1-4C-alkoxy-ethoxy, 1-2C-alkylthio, hydroxyl,    amino, or mono- or di-1-2C-alkylamino,-   R8 is halogen;    and the salts, the N-oxides and the salts of the N-oxides of these    compounds.

Compounds of formula I according to aspect B in more particular worthyto be mentioned in a sub-aspect (subaspect B3) are those in which

-   R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,    in one embodimental detail according to this invention,-   Har is optionally substituted by R6 and/or R7, and is a 9- or    10-membered benzofused bicyclic partially saturated heteroaryl    radical comprising 1 or 2 heteroatoms selected independently from    the group consisting of oxygen, nitrogen and sulfur, in which-   R6 is 1-2C-alkyl or halogen,-   R7 is halogen;    or, in another embodimental detail according to this invention,-   Har is optionally substituted by R6, and is a 9- or 10-membered    fused bicyclic unsaturated heteroaryl radical comprising 1 to 3    heteroatoms selected independently from the group consisting of    oxygen, nitrogen and sulfur, in which-   R6 is 1-4C-alkyl;    or, in yet another embodimental detail according to this invention,    either-   Har is optionally substituted by R6, and is a 5-membered monocyclic    unsaturated heteroaryl radical comprising 1 to 3 heteroatoms    selected independently from the group consisting of oxygen, nitrogen    and sulfur, in which-   R6 is 1-4C-alkyl or pyridyl,    or-   Har is optionally substituted by R6 and/or R7, and is a 6-membered    monocyclic unsaturated heteroaryl radical comprising 1 or 2 nitrogen    atoms, in which-   R6 is 1-4C-alkoxy, 1-2C-alkoxy-ethoxy or -A-N(R61)R62, in which-   A is a bond,-   R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either, in one facet,-   Het1 is optionally substituted by R611 on a ring nitrogen atom, and    is a 5- to 7-membered saturated monocyclic heterocyclic ring radical    comprising the nitrogen atom, to which R61 and R62 are bonded, and    optionally one further heteroatom selected from the group consisting    of oxygen, nitrogen and sulfur, in which-   R611 is 1-2C-alkyl,    or, in another facet,-   Het1 is a 5-membered unsaturated monocyclic heterocyclic ring    radical comprising the nitrogen atom, to which R61 and R62 are    bonded, and optionally one or two further nitrogen atoms,-   R7 is 1-4C-alkoxy or 1-2C-alkoxy-ethoxy;    and the salts, the N-oxides and the salts of the N-oxides of these    compounds.

Compounds of formula I according to aspect B in still more particularworthy to be mentioned in a sub-aspect (subaspect B4) are those in which

-   R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,    in one embodimental detail according to this invention,-   Har is optionally substituted by R6 and/or R7, and is    benzo[1,4]dioxanyl or benzo[1,3]dioxolyl, in which-   R6 is fluorine,-   R7 is fluorine;    or, in another embodimental detail according to this invention,-   Har is quinolinyl, benzofurazanyl or benzothiazolyl;    or, in yet another embodimental detail according to this invention,    either-   Har is optionally substituted by R6 and/or R7, and is pyridinyl, in    which-   R6 is 1-4C-alkoxy, -A-N(R61)R62, in which-   A is a bond,-   R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which-   Het1 is morpholinyl, thiomorpholinyl, N—(R611)-piperazinyl or    4-N—(R611)-homopiperazinyl, in which-   R611 is 1-2C-alkyl,-   R7 is 1-4C-alkoxy,    or-   Har is optionally substituted by R6, and is isoxazolyl, imidazolyl    or thiazolyl, in which-   R6 is 1-4C-alkyl or pyridyl;    and the salts, the N-oxides and the salts of the N-oxides of these    compounds.

Compounds of formula I according to aspect C more worthy to be mentionedin a sub-aspect (subaspect C1) are those, in which

-   R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    2,2-difluoroethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen,    either, in a first embodiment (embodiment a) according to the    present invention,-   R4 is —O—R41, in which-   R41 is hydrogen or 1-4C-alkylcarbonyl, and-   R5 is hydrogen,    or, in a second embodiment (embodiment b) according to the present    invention,-   R4 is hydrogen, and-   R5 is —O—R51, in which-   R51 is hydrogen or 1-4C-alkylcarbonyl,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radical, in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, sulfanyl, cyano, 1-4C-alkoxycarbonyl, carboxyl,    hydroxyl, oxo, or -A-N(R61)R62, in which-   A is a bond or 1-4C-alkylene,-   R61 is hydrogen or 1-4C-alkyl,-   R62 is hydrogen or 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl,    thiomorpholin-4-yl, piperazin-1-yl or    4N-(1-4C-alkyl)-piperazin-1-yl,    or-   Het1 is pyrrol-1-yl, pyrazol-1-yl, triazol-1-yl, or imidazol-1-yl,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkylthio, sulfanyl, hydroxyl, oxo, amino or    di-1-4C-alkylamino,-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect C in particular worthy to bementioned in a sub-aspect (subaspect C2) are those, in which

-   R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen or 1-4C-alkylcarbonyl,-   R5 is hydrogen,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radical, in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio,    1-4C-alkoxycarbonyl, carboxyl, hydroxyl, oxo, or -A-N(R61)R62, in    which-   A is a bond or 1-4C-alkylene,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl,    thiomorpholin-4-yl, piperazin-1-yl or 4N-methyl-piperazin-1-yl,    or-   Het1 is pyrrol-f-yl, pyrazol-1-yl, triazol-1-yl or imidazol-1-yl,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, hydroxyl, oxo, or    di-1-4C-alkylamino,-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect C in more particular worthyto be mentioned in a sub-aspect (subaspect C3) are those, in which oneof R1 and R2 is methoxy or ethoxy, and the other is methoxy, ethoxy,difluoromethoxy or 2,2-difluoroethoxy, and

-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is optionally substituted by R6 and/or R7 and/or R8, and is a    pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl radical, in which-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio,    1-4C-alkoxycarbonyl, carboxyl, hydroxyl, oxo, or -A-N(R61)R62, in    which-   A is a bond or 1-2C-alkylene,-   R61 is 1-4C-alkyl,-   R62 is 1-4C-alkyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl or morpholin-4-yl,    or-   Het1 is pyrazol-1-yl or imidazol-1-yl,-   R7 is 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, hydroxyl, oxo, or    di-1-4C-alkylamino,-   R8 is halogen or 1-4C-alkoxy,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect C in still more particularworthy to be mentioned in a sub-aspect (subaspect C4) are those, inwhich

-   R1 is methoxy or ethoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is substituted by R6, and is a pyridinyl, pyrimidinyl, pyrazinyl    or pyridazinyl radical, in which-   R6 is methyl, methoxy, ethoxy, methylthio, methoxycarbonyl,    carboxyl, hydroxyl, or -A-N(R61)R62, in which-   A is a bond, methylene or ethylene,-   R61 is methyl,-   R62 is methyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl or morpholin-4-yl,    or-   Het1 is pyrazol-1-yl or imidazol-1-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Particular compounds of formula I according to subaspect C4 of thisinvention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is substituted by R6, and is pyridinyl, in which-   R6 is methoxy, ethoxy, methylthio, methoxycarbonyl, hydroxyl,    carboxyl, or -A-N(R61)R62, in which-   A is a bond, or ethylene,-   R61 is methyl,-   R62 is methyl,-   or R61 and R62 together and with inclusion of the nitrogen atom, to    which they are attached, form a heterocyclic ring Het1, in which    either-   Het1 is piperidin-1-yl, pyrrolidin-1-yl or morpholin-4-yl,    or-   Het1 is pyrazol-1-yl or imidazol-1-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Other particular compounds of formula I according to subaspect C4 ofthis invention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is substituted by R6, and is pyrimidinyl, in which-   R6 is methoxy, ethoxy, methylthio, or -A-N(R61)R62, in which-   A is a bond,-   R61 is methyl,-   R62 is methyl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

More particular compounds of formula I according to subaspect C4 of thisinvention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is 6-(morpholin-4-yl)-pyridin-3-yl,    6-(piperidin-1-yl)-pyridin-3-yl, 6-(pyrazol-1-yl)-pyridin-3-yl,    6-(imidazol-1-yl)-pyridin-3-yl, 6-methoxycarbonyl-pyridin-3-yl,    3-methoxycarbonyl-pyridin-2-yl, 2-methoxy-pyridin-3-yl,    6-methoxy-pyridin-3-yl, 2-methylsulfanyl-pyridin-3-yl,    6-hydroxy-pyridin-3-yl, 6-carboxy-pyridin-3-yl,    2-methoxy-pyrimidin-5-yl, 2-dimethylamino-pyrimidin-5-yl,    2-methylsulfanyl-pyrimidin-5-yl, 5-methyl-pyrazin-2-yl, or    6-[2-(pyrrolidin-1-yl)-ethyl]-pyridin-3yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to subaspect C4 of this invention to beemphasized are those, in which

-   R1 is methoxy,-   R2 is ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is methoxy-pyrimidinyl, methylthio-pyrimidinyl,    dimethylamino-pyrimidinyl, or imidazol-1-yl-pyridinyl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect C4 of this invention to bemore emphasized are those, in which

-   R1 is methoxy,-   R2 is ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is 6-(imidazol-1-yl)-pyridin-3-yl, 2-methoxy-pyrimidin-5-yl,    2-dimethylamino-pyrimidin-5-yl, or 2-methylsulfanyl-pyrimidin-5-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Further compounds of formula I according to aspect C in still moreparticular worthy to be mentioned in a sub-aspect (subaspect C5) arethose, in which

-   R1 is methoxy or ethoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,    either-   Har is substituted by R6 and R7, and is a pyridinyl, pyrimidinyl,    pyrazinyl or pyridazinyl radical, in which-   R6 is chlorine, methoxy, ethoxy, methylthio, oxo, or -A-N(R61)R62,    in which-   A is a bond,-   R61 is methyl,-   R62 is methyl, and-   R7 is methyl, methoxy, ethoxy, methylthio, or dimethylamino,    or-   Har is substituted by R6 and R8, and is a pyridinyl, pyrimidinyl,    pyrazinyl or pyridazinyl radical, in which-   R6 is -A-N(R61)R62, in which-   A is a bond,-   R61 is methyl,-   R62 is methyl, and-   R8 is chlorine,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Particular compounds of formula I according to subaspect C5 of thisinvention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,    either-   Har is substituted by R6 and R7, and is a pyridinyl, pyrimidinyl,    pyridazinyl or pyrazinyl radical, in which-   R6 is methoxy or ethoxy, and-   R7 is methoxy or ethoxy,    or-   R6 is oxo, and-   R7 is methyl,    or-   R6 is methylthio, and-   R7 is methyl,    or-   R6 is chlorine, and-   R7 is methylthio,    or-   R6 is dimethylamino, and-   R7 is methoxy or ethoxy,    or-   R6 is dimethylamino, and-   R7 is dimethylamino,    or-   Har is substituted by R6 and R8, and is a pyridinyl, pyrimidinyl,    pyridazinyl or pyrazinyl radical, in which-   R6 is dimethylamino, and-   R8 is chlorine,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

More particular compounds of formula I according to subaspect C5 of thisinvention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is substituted by R6 and R7, and is pyridinyl, in which    either-   R6 is methoxy or ethoxy, and-   R7 is methoxy or ethoxy,    or-   R6 is oxo, and-   R7 is methyl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Other more particular compounds of formula I according to subaspect C5of this invention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,    either-   Har is substituted by R6 and R7, and is pyrimidinyl, in which-   R6 is methoxy or ethoxy, and-   R7 is methoxy or ethoxy,    or-   R6 is oxo, and-   R7 is methyl,    or-   R6 is methylthio, and-   R7 is methyl,    or-   R6 is chlorine, and-   R7 is methylthio,    or-   R6 is dimethylamino, and-   R7 is methoxy or ethoxy,    or-   Har is substituted by R6 and R8, and is pyrimidinyl, in which-   R6 is dimethylamino, and-   R8 is chlorine,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Other more particular compounds of formula I according to subaspect C5of this invention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is substituted by R6 and R7, and is pyridazinyl, in which-   R6 is methoxy or ethoxy, and-   R7 is methoxy or ethoxy,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Yet more particular compounds of formula I according to subaspect C5 ofthis invention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is 2,6-dimethoxy-pyridin-3-yl, 2,6-dimethoxy-pyridin-4-yl,    4,6-dimethoxy-pyridin-3-yl, 5,6-dimethoxy-pyridin-3-yl,    4,6-diethoxy-pyridin-3-yl, 5-ethoxy-6-methoxy-pyridin-3-yl,    1-methyl-1H-pyridin-2-one-5-yl, 2,6-dimethoxy-pyrimidin-4-yl,    2,4-dimethoxy-pyrimidin-5-yl, 4,6-dimethoxy-pyrimidin-5-yl,    4-methyl-2-methylsulfanyl-pyrimidin-5-yl,    5-chloro-2-methylsulfanyl-pyrimidin-4-yl,    4-chloro-2-dimethylamino-pyrimidin-5-yl,    2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl, or 3,6-dimethoxy-pyridazin-4-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect C5 of this invention to beemphasized are those, in which

-   R1 is methoxy,-   R2 is ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is dimethoxypyrimidinyl, dimethoxypyridinyl,    dimethoxypyridazinyl, N-methylpyridonyl, N-methylpyrimidonyl, or    methoxy-dimethylamino-pyrimidinyl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to subaspect C5 of this invention to bemore emphasized are those, in which

-   R1 is methoxy,-   R2 is ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is 2,6-dimethoxy-pyrimidin-4-yl, 2,4-dimethoxy-pyrimidin-5-yl,    4,6-dimethoxy-pyrimidin-5-yl, 2,6-dimethoxy-pyridin-3-yl,    2,6-dimethoxy-pyridin-4-yl, 4,6-dimethoxy-pyridin-3-yl,    5,6-dimethoxy-pyridin-3-yl, 3,6-dimethoxy-pyridazin-4-yl,    1-methyl-1H-pyridin-2-one-5-yl, 1-methyl-1H-pyrimidin-2-one-5-yl, or    2-dimethylamino-4-methoxy-pyrimidin-5-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Further compounds of formula I according to aspect C in still moreparticular worthy to be mentioned in a sub-aspect (subaspect C6) arethose, in which

-   R1 is methoxy or ethoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is substituted by R6 and R7 and R8, and is a pyridinyl,    pyrimidinyl, pyrazinyl or pyridazinyl radical, in which-   R6 is methoxy, or dimethylamino,-   R7 is methoxy, or dimethylamino,-   R8 is chlorine or methoxy,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Particular compounds of formula I according to subaspect C6 of thisinvention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,    either-   Har is substituted by R6 and R7 and R8, and is pyridinyl, in which-   R6 is methoxy,-   R7 is methoxy,-   R8 is chlorine,    or-   Har is substituted by R6 and R7 and R8, and is pyrimidinyl, in which-   R6 is methoxy,-   R7 is methoxy,-   R8 is methoxy,    or-   Har is substituted by R6 and R7 and R8, and is pyrimidinyl, in which-   R6 is dimethylamino,-   R7 is dimethylamino,-   R8 is chlorine,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

More particular compounds of formula I according to subaspect C6 of thisinvention are those, in which

-   R1 is methoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is 3-chloro-2,6-dimethoxy-pyridin-4-yl,    4-chloro-2,6-dimethoxy-pyridin-3-yl,    2,4,6-trimethoxy-pyrimidin-5-yl, or    5-chloro-2,6-bisdimethylamino-pyrimidin-4-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Further compounds of formula I according to aspect C in still moreparticular worthy to be mentioned in a sub-aspect (subaspect C7) arethose, in which

-   R1 is methoxy or ethoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is unsubstituted, and is a pyridinyl, pyrimidinyl, pyrazinyl or    pyridazinyl radical,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Particular compounds of formula I according to subaspect C7 of thisinvention are those, in which

-   R1 is methoxy or ethoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is unsubstituted, and is pyridin-3-yl, pyridin-4-yl,    pyrimidin-5-yl, or pyrazin-2-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

More particular compounds of formula I according to subaspect C7 of thisinvention are those, in which

-   R1 is methoxy or ethoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is unsubstituted, and is pyridin-3-yl, pyridin-4-yl,    pyrimidin-5-yl, or pyrazin-2-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect C to be emphasized in asub-aspect (subaspect C8) are those, in which

-   R1 is methoxy or ethoxy,-   R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is any one selected from-   pyridin-3-yl, pyridin-4-yl,-   6-(morpholin-4-yl)-pyridin-3-yl, 6-(piperidin-1-yl)-pyridin-3-yl,    6-(pyrazol-1-yl)-pyridin-3-yl, 6-(imidazol-1-yl)-pyridin-3-yl,-   6-methoxycarbonyl-pyridin-3-yl, 3-methoxycarbonyl-pyridin-2-yl,-   2-methoxy-pyridin-3-yl, 6-methoxy-pyridin-3-yl,-   2-methylsulfanyl-pyridin-3-yl,-   6-hydroxy-pyridin-3-yl, 6-carboxy-pyridin-3-yl,-   pyrimidin-5-yl,-   2-methoxy-pyrimidin-5-yl, 2-dimethylamino-pyrimidin-5-yl,    2-methylsulfanyl-pyrimidin-5-yl, pyrazin-2-yl,    5-methyl-pyrazin-2-yl,-   6-[2-(pyrrolidin-1-yl)-ethyl]-pyridin-3-yl,-   2,6-dimethoxy-pyridin-3-yl, 2,6-dimethoxy-pyridin-4-yl,    4,6-dimethoxy-pyridin-3-yl, 5,6-dimethoxy-pyridin-3-yl,    4,6-diethoxy-pyridin-3-yl, 5-ethoxy-6-methoxy-pyridin-3-yl,-   1-methyl-1H-pyridin-2-one-5-yl,-   2,6-dimethoxy-pyrimidin-4-yl, 2,4-dimethoxy-pyrimidin-5-yl,    4,6-dimethoxy-pyrimidin-5-yl,    4-methyl-2-methylsulfanyl-pyrimidin-5-yl,    5-chloro-2-methylsulfanyl-pyrimidin-4-yl,    4-chloro-2-dimethylamino-pyrimidin-5-yl,    2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl,-   3,6-dimethoxy-pyridazin-4-yl-   4-chloro-2,6-dimethoxy-pyridin-3-yl,    3-chloro-2,6-dimethoxy-pyridin-4-yl,    5-chloro-2,6-bisdimethylamino-pyrimidin-4-yl, and-   2,4,6-trimethoxy-pyrimidin-5-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect C to be more emphasized in asub-aspect (subaspect C9) are those, in which

-   R1 is methoxy,-   R2 is ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is any one selected from-   pyridin-3-yl, pyridin-4-yl,-   6-(morpholin-4-yl)-pyridin-3-yl, 6-(piperidin-1-yl)-pyridin-3-yl,    6-(pyrazol-1-yl)-pyridin-3-yl, 6-(imidazol-1-yl)-pyridin-3-yl,-   6-methoxycarbonyl-pyridin-3-yl, 3-methoxycarbonyl-pyridin-2-yl,-   2-methoxy-pyridin-3-yl, 6-methoxy-pyridin-3-yl,-   2-methylsulfanyl-pyridin-3-yl,-   6-hydroxy-pyridin-3-yl, 6-carboxy-pyridin-3-yl-   pyrimidin-5-yl,-   2-methoxy-pyrimidin-5-yl, 2-dimethylamino-pyrimidin-5-yl,    2-methylsulfanyl-pyrimidin-5-yl, pyrazin-2-yl,    5-methyl-pyrazin-2-yl,-   2,6-dimethoxy-pyridin-3-yl, 2,6-dimethoxy-pyridin-4-yl,    4,6-dimethoxy-pyridin-3-yl, 5,6-dimethoxy-pyridin-3-yl,    4,6-diethoxy-pyridin-3-yl, 5-ethoxy-6-methoxy-pyridin-3-yl,-   1-methyl-1H-pyridin-2-one-5-yl,-   2,6-dimethoxy-pyrimidin-4-yl, 2,4-dimethoxy-pyrimidin-5-yl,    4,6-dimethoxy-pyrimidin-5-yl,-   4-methyl-2-methylsulfanyl-pyrimidin-5-yl,    5-chloro-2-methylsulfanyl-pyrimidin-4-yl,    4-chloro-2-dimethylamino-pyrimidin-5-yl;    2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl,-   3,6-dimethoxy-pyridazin-4-yl-   4-chloro-2,6-dimethoxy-pyridin-3-yl,    3-chloro-2,6-dimethoxy-pyridin-4-yl,    5-chloro-2,6-bisdimethylamino-pyrimidin-4-yl, and-   2,4,6-trimethoxy-pyrimidin-5-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect C to be in particularemphasized in a sub-aspect (subaspect C10) are those, in which

-   R1 is methoxy,-   R2 is ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is any one selected from-   6-(imidazol-1-yl)-pyridin-3-yl, pyrimidin-5-yl,-   2-methoxy-pyrimidin-5-yl, 2-dimethylamino-pyrimidin-5-yl,    2-methylsulfanyl-pyrimidin-5-yl, 2,6-dimethoxy-pyridin-3-yl,    2,6-dimethoxy-pyridin-4-yl, 4,6-dimethoxy-pyridin-3-yl,    5,6-dimethoxy-pyridin-3-yl, 4,6-diethoxy-pyridin-3-yl,    5-ethoxy-6-methoxy-pyridin-3-yl,-   1-methyl-1H-pyridin-2-one-5-yl,-   2,6-dimethoxy-pyrimidin-4-yl, 2,4-dimethoxy-pyrimidin-5-yl,    4,6-dimethoxy-pyrimidin-5-yl,-   2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl, and-   3,6-dimethoxy-pyridazin-4-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

Compounds of formula I according to aspect C to be in more particularemphasized in a sub-aspect (subaspect C11) are those, in which

-   R1 is methoxy,-   R2 is ethoxy, difluoromethoxy or 2,2-difluoroethoxy,-   R3 is hydrogen,-   R31 is hydrogen,-   R4 is —O—R41, in which-   R41 is hydrogen,-   R5 is hydrogen,-   Har is any one selected from-   6-(imidazol-1-yl)-pyridin-3-yl, pyrimidin-5-yl,-   2-methoxy-pyrimidin-5-yl, 2-dimethylamino-pyrimidin-5-yl,    2-methylsulfanyl-pyrimidin-5-yl,-   2,6-dimethoxy-pyridin-3-yl, 4,6-dimethoxy-pyridin-3-yl,    1-methyl-1H-pyridin-2-one-5-yl,-   2,4-dimethoxy-pyrimidin-5-yl,    2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl, and 3,6-dimethoxy-pyridazin-4-yl,    and the enantiomers, as well as the salts, the N-oxides and the    salts of the N-oxides of these compounds and enantiomers.

A special interest in the compounds according to this invention relatesto those compounds which are included—within the meaning of thisinvention—by one or, when possible, by more of the followingembodiments:

A special embodiment of the compounds of the present invention includethose compounds of formula I in which R1 and R2 are independently1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantlyfluorine-substituted 1-2C-alkoxy.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 and R2 areindependently 1-2C-alkoxy, 2,2-difluoroethoxy, or completely orpredominantly fluorine-substituted 1-2C-alkoxy, and R3 and R31 are bothhydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which one of R1 and R2 ismethoxy, and the other is methoxy, ethoxy, difluoromethoxy or2,2-difluoroethoxy, and

-   R3 and R31 are both hydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is ethoxy or,particularly, methoxy, and R2 is methoxy, or, particularly, ethoxy,difluoromethoxy or 2,2-difluoroethoxy, and R3 and R31 are both hydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is methoxy, and R2 ismethoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy, and R3 and R31are both hydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is methoxy, and R2 isethoxy, difluoromethoxy or 2,2-difluoroethoxy, and R3 and R31 are bothhydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which one of R1 and R2 is2,2-difluoroethoxy, and the other is different from 2,2-difluoroethoxy,and R3 and R31 are both hydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is ethoxy or,particularly, methoxy, and R2 is 2,2-difluoroethoxy, and R3 and R31 areboth hydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is methoxy, and R2 is2,2-difluoroethoxy, and R3 and R31 are both hydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is methoxy, and R2 isethoxy, and R3 and R31 are both hydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is methoxy, and R2 isdifluoromethoxy, and R3 and R31 are both hydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which R5 or, particularly, R4is the radical (1-4C-alkylcarbonyl)-O— such as e.g. acetoxy, orhydroxyl, and all the other substituents are as defined in any compoundwhich is said to be mentioned above in aspect A or B or C, or in any oneof the sub-aspects thereof.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R5 or, particularly, R4 ishydroxyl.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is optionallysubstituted by R6 and/or R7 and/or R8, and is

-   -   a 9- or 10-membered fused bicyclic partially saturated        heteroaryl radical comprising a benzene ring and 1 or 2        heteroatoms independently selected from the group consisting of        oxygen, nitrogen and sulphur, or    -   a 9- or 10-membered fused bicyclic unsaturated heteroaryl        radical comprising 1 to 4, particularly 1, 2 or 3, heteroatoms        independently selected from the group consisting of oxygen,        nitrogen and sulphur, or    -   a 6-membered monocyclic unsaturated heteroaryl radical        comprising 1 to 3, particularly 1 or 2, nitrogen atoms, or    -   a 5-membered monocyclic unsaturated heteroaryl radical        comprising 1 to 4, particularly 1, 2 or 3, heteroatoms        independently selected from the group consisting of oxygen,        nitrogen and sulphur,        in which

-   R6 is halogen, 1-4C-alkyl, 1-4C-alkoxy, cyano, oxo,    1-4C-alkoxycarbonyl, pyridyl, morpholino, piperidino, imidazol-1-yl    or pyrazol-1-yl,

-   R7 is 1-4C-alkyl or 1-4C-alkoxy,

-   R8 is halogen, 1-4C-alkyl or 1-4C-alkoxy.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is

-   benzo[1,4]dioxanyl, benzo[1,3]dioxolyl or    2,2-difluoro-benzo[1,3]dioxolyl;-   quinolinyl, benzofurazanyl, benzothiazolyl,    1-methyl-1H-benzotriazolyl or    4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridinyl; or-   pyridinyl, pyrimidinyl, pyrazinyl, 5-methyl-pyrazinyl, isoxazolyl,    1-methyl-imidazolyl, 2-(pyridinyl)-thiazolyl,-   2,6-dimethoxy-pyridinyl, 2-methoxy-pyridinyl,-   6-(methoxycarbonyl)-pyridinyl, 5-(methoxycarbonyl)-pyridinyl,-   2,6-dimethoxypyrimidinyl, 2-methoxy-pyrimidinyl,    2,4,6-trimethoxy-pyrimidinyl, 2,4-dimethoxy-pyrimidinyl,-   6-(morpholin-4-yl)-pyridinyl, 6-(piperidin-1-yl)-pyridinyl,    6-(pyrazol-1-yl)-pyridinyl, 6-(imidazol-1-yl)-pyridinyl, or-   3-chloro-2,6-dimethoxy-pyridinyl.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is

-   benzo[1,4]dioxan-6-yl, benzo[1,3]dioxol-5-yl or    2,2-difluoro-benzo[1,3]dioxol-5-yl;-   quinolin-6-yl, benzofurazan-5-yl, benzothiazol-6-yl,    1-methyl-1H-benzotriazol-5-yl or    4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl; or-   pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl,    5-methyl-pyrazin-2-yl, isoxazol-5-yl, 1-methyl-imidazol-2-yl,    1-methyl-imidazol-5-yl, 2-(pyridin-3-yl)-thiazol-4-yl,-   2,6-dimethoxy-pyridin-4-yl, 2,6-dimethoxy-pyridin-3-yl,    2-methoxy-pyridin-3-yl,-   6-(methoxycarbonyl)-pyridin-3-yl, 5-(methoxycarbonyl)-pyridin-2-yl,-   2,6-dimethoxypyrimidin-4-yl, 2-methoxy-pyrimidin-5-yl,    2,4,6-trimethoxy-pyrimidin-5-yl, 2,4-dimethoxy-pyrimidin-5-yl,    2,6-dimethoxy-pyrimidin-4-yl,-   6-(morpholin-4-yl)-pyridin-3-yl, 6-(piperidin-1-yl)-pyridin-3-yl,    6-(pyrazol-1-yl)-pyridin-3-yl, 6-(imidazol-1-yl)-pyridin-3-yl, or-   3-chloro-2,6-dimethoxy-pyridin-4-yl.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is optionallysubstituted by R6 and/or R7 and/or R8, and is pyridinyl, pyrazinyl,pyridazinyl or pyrimidinyl, in which R6, R7, R8 and all the othersubstituents are as defined in any compound which is disclosed herein,such as e.g. any compound which is said to be mentioned above in aspectA or B or C, or in any One of the sub-aspects thereof.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is optionallysubstituted by R6 and/or R7 and/or R8, and is pyridinyl, in which R6,R7, R8 and all the other substituents are as defined in any compoundwhich is disclosed herein.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which

-   Har is substituted by R6 and R7 and R8, or-   Har is substituted by R6 and R7, or-   Har is substituted by R6 and R8, or-   Har is substituted by R7 and R8, and is pyridinyl, in which R6, R7,    R8 and all the other substituents are as defined in any compound    which is disclosed herein.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which

-   Har is substituted by R6 and R7, and is pyridinyl, in which R6 and    R7 and all the other substituents are as defined in any compound    which is disclosed herein.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is optionallysubstituted by R6 and/or R7 and/or R8, and is pyrimidinyl, in which R6,R7, R8 and all the other substituents are as defined in any compoundwhich is disclosed herein.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I; in which Har is optionallysubstituted by R6 and/or R7, and is pyrimidinyl or pyridazinyl, in whichR6 and R7 and all the other substituents are as defined in any compoundwhich is disclosed herein.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which R6 and/or R7 is an oxogroup.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, each of which is substituted byR6 and/or R7 and/or R8, in which

-   R6 or R7 is an oxo group, and one of the other substituents is    1-4C-alkyl, e.g. methyl, bonded to a ring nitrogen atom to form a    cyclic amide structure.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which R6 and/or R7 is a1-4C-alkylthio, such as e.g. methylthio, group.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which R6 is -A-N(R61)R62, inwhich

-   A is a bond, and R61 and R62 together and with inclusion of the    nitrogen atom to which they are attached, form a heterocyclic ring    Het1, particularly Het1 according to facet 2, such as e.g.    pyrrol-1-yl, triazol-1-yl or, especially, pyrazol-1-yl or    imidazol-1-yl.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which A is a bond.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is substituted by R6and/or R7, and is pyridinyl, in which,

-   R6 is 1-4C-alkoxy, 1-4C-alkoxycarbonyl or carboxyl,-   R7 is 1-4C-alkoxy.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which

either

-   Har is N-methyl-pyridonyl or N-methyl-pyrimidonyl,    -   or-   Har is substituted by R6, and is pyridinyl or pyrimidinyl, in which-   R6 is imidazol-1-yl-pyridinyl, pyrazol-1-yl-pyridinyl, methylthio,    methoxy, ethoxy, dimethylamino,    -   or-   Har is substituted by R6 and R7, and is pyridinyl, pyrimidinyl or    pyridazinyl, in which-   R6 is methoxy, ethoxy or dimethylamino, and-   R7 is methoxy or ethoxy.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which

-   Har is either N-methyl-pyrid-2-onyl or N-methyl-pyrimid-2-onyl,    -   or imidazol-1-yl-pyridinyl or pyrazol-1-yl-pyridinyl,    -   or methylthio-pyrimidinyl, methoxy-pyrimidinyl,        dimethylamino-pyrimidinyl or pyrimidinyl,    -   or-   Har is substituted by R6 and R7, and is pyridinyl, in which-   R6 is methoxy or ethoxy, and-   R7 is methoxy or ethoxy,    -   or-   Har is substituted by R6 and R7, and is pyrimidinyl or pyridazinyl,    in which-   R6 is methoxy, ethoxy or dimethylamino, and-   R7 is methoxy or ethoxy.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyridinylbisubstituted by 1-4C-alkoxy, such as, for example,2,6-dimethoxypyridinyl (e.g. 2,6-dimethoxypyridin-3-yl).

A preferred embodiment according to the present invention is embodimenta.

A further preferred embodiment of the compounds of the present inventioninclude compounds according to embodiment a, in which R5 and R41 areboth hydrogen, and in which R1 and R2 are independently 1-2C-alkoxy,2,2-difluoroethoxy, or completely or predominantly fluorine-substituted1-2-C-alkoxy, and R3 and R31 are hydrogen.

A yet further preferred embodiment of the compounds of the presentinvention include compounds according to embodiment a, in which R5 ishydrogen, and in which R1 is methoxy, and R2 is ethoxy, difluoromethoxyor 2,2-difluoroethoxy, and R3 and R31 are both hydrogen.

A still yet further preferred embodiment of the compounds of the presentinvention include compounds according to embodiment a, in which R5 andR41 are both hydrogen, and in which R1 is methoxy, and R2 is ethoxy,difluoromethoxy or 2,2-difluoroethoxy, and R3 and R31 are both hydrogen.

Another preferred embodiment according to the present invention isaspect C.

In this context, a special embodiment of the compounds of the presentinvention include those compounds of formula I, in which Har ispyridinyl substituted by R6 and R7, in which

-   R6 is 1-4C-alkoxy, particularly methoxy or ethoxy,-   R7 is 1-4C-alkoxy, particularly methoxy or ethoxy,    such as, for example, dimethoxy-pyridinyl or    ethoxy-(methoxy-)pyridinyl, e.g. dimethoxy-pyridin-3-yl or    dimethoxy-pyridin-4-yl or ethoxy-(methoxy-)pyridine-3-yl, like    2,6-dimethoxy-pyridin-3-yl, 2,6-dimethoxy-pyridin-4-yl,    4,6-dimethoxy-pyridin-3-yl, 5,6-dimethoxy-pyridin-3-yl,    4,6-diethoxy-pyridin-3-yl, or 5-ethoxy-6-methoxy-pyridin-3-yl.

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyrimidinylmonosubstituted by 1-4C-alkoxy, particularly methoxy or ethoxy, such as,for example, methoxy-pyrimidinyl, e.g. methoxy-pyrimidin-5-yl, like2-methoxy-pyrimidin-5-yl.

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyrimidinylmonosubstituted by di-1-4C-alkylamino, particularly di-1-2C-alkylamino,such as, for example, dimethylamino-pyrimidinyl, e.g.dimethylamino-pyrimidin-5-yl, like 2-dimethylamino-pyrimidin-5-yl.

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyrimidinylsubstituted by R6 and R7, in which

-   R6 is 1-4C-alkoxy, particularly methoxy or ethoxy,-   R7 is 1-4C-alkoxy, particularly methoxy or ethoxy,    such as, for example, dimethoxy-pyrimidinyl, e.g.    dimethoxy-pyrimidin-5-yl or dimethoxy-pyrimidin-4-yl, like    2,6-dimethoxy-pyrimidin-4-yl, 2,4-dimethoxy-pyrimidin-5-yl, or    4,6-dimethoxy-pyrimidin-5-yl.

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyridazinylsubstituted by R6 and R7, in which

-   R6 is 1-4C-alkoxy, particularly methoxy or ethoxy,-   R7 is 1-4C-alkoxy, particularly methoxy or ethoxy,    such as, for example, dimethoxy-pyridazinyl, e.g.    dimethoxy-pyridazin-4-yl, like 3,6-dimethoxy-pyridazin-4-yl.

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyrimidinylsubstituted by R6 and R7, in which

-   R6 is 1-2C-alkoxy, particularly methoxy,-   R7 is di-1-2C-alkylamino, particularly dimethylamino,    such as, for example, methoxy-(dimethylamino-)pyrimidinyl, e.g.    methoxy-(dimethylamino-)pyrimidin-5-yl, like    4-methoxy-2-dimethylamino-pyrimidin-5-yl.

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har isN-(1-4C-alkyl)-pyridonyl, such as, for example, N-methyl-pyridonyl, e.g.1-methyl-1H-pyridin-2-onyl, like 1-methyl-1H-pyridin-2-one-5-yl (i.e.1-methyl-6-oxo-1H-pyridin-3-yl).

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har isN-(1-4C-alkyl)-pyrimidonyl, such as, for example, N-methyl-pyrimidonyl,e.g. 1-methyl-1H-pyrimidin-2-onyl, like 1-methyl-1H-pyrimidin-2-one-5-yl(i.e. 1-methyl-2-oxo-1H-pyrimidin-5-yl).

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyridinylsubstituted by two methoxy radicals, such as, for example,2,6-dimethoxy-pyridin-3-yl.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyrimidinylsubstituted by two methoxy radicals, such as; for example,2,4-dimethoxy-pyrimidin-5-yl.

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyrimidinylmonosubstituted by methoxy, such as, for example,2-methoxy-pyrimidin-5-yl.

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is pyridazinylsubstituted by two methoxy radicals, such as, for example,3,6-dimethoxy-pyridazin-4-yl.

A further special embodiment of the compounds of the present inventioninclude those compounds of formula I, in which Har is

-   pyridin-3-yl, pyridin-4-yl,-   6-(morpholin-4-yl)-pyridin-3-yl, 6-(piperidin-1-yl)-pyridin-3-yl,    6-(pyrazol-1-yl)-pyridin-3-yl, 6-(imidazol-1-yl)-pyridin-3-yl,-   6-methoxycarbonyl-pyridin-3-yl, 3-methoxycarbonyl-pyridin-2-yl,-   2-methoxy-pyridin-3-yl, 6-methoxy-pyridin-3-yl,-   2-methylsulfanyl-pyridin-3-yl,-   6-hydroxy-pyridin-3-yl, 6-carboxy-pyridin-3-yl, pyrimidin-5-yl,-   2-methoxy-pyrimidin-5-yl, 2-dimethylamino-pyrimidin-5-yl,    2-methylsulfanyl-pyrimidin-5-yl, pyrazin-2-yl,    5-methyl-pyrazin-2-yl,-   6-[2-(pyrrolidin-1-yl)-ethyl]-pyridin-3-yl,-   2,6-dimethoxy-pyridin-3-yl, 2,6-dimethoxy-pyridin-4-yl,    4,6-dimethoxy-pyridin-3-yl, 5,6-dimethoxy-pyridin-3-yl,    4,6-diethoxy-pyridin-3-yl, 5-ethoxy-6-methoxy-pyridin-3-yl,-   1-methyl-1H-pyridin-2-one-5-yl,-   2,6-dimethoxy-pyrimidin-4-yl, 2,4-dimethoxy-pyrimidin-5-yl,    4,6-dimethoxy-pyrimidin-5-yl,-   4-methyl-2-methylsulfanyl-pyrimidin-5-yl,    5-chloro-2-methylsulfanyl-pyrimidin-4-yl,    4-chloro-2-dimethylamino-pyrimidin-5-yl,    2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl,-   3,6-dimethoxy-pyridazin-4-yl,-   4-chloro-2,6-dimethoxy-pyridin-3-yl,    3-chloro-2,6-dimethoxy-pyridin-4-yl,    5-chloro-2,6-bisdimethylamino-pyrimidin-4-yl, or-   2,4,6-trimethoxy-pyrimidin-5-yl.

A yet further special embodiment of the compounds of the presentinvention include those compounds of formula I, in which Har is

-   6-(imidazol-1-yl)-pyridin-3-yl, pyrimidin-5-yl,-   2-methoxy-pyrimidin-5-yl, 2-dimethylamino-pyrimidin-5-yl,    2-methylsulfanyl-pyrimidin-5-yl,-   2,6-dimethoxy-pyridin-3-yl, 2,6-dimethoxy-pyridin-4-yl,    4,6-dimethoxy-pyridin-3-yl, 5,6-dimethoxy-pyridin-3-yl,    4,6-diethoxy-pyridin-3-yl, 5-ethoxy-6-methoxy-pyridin-3-yl,-   1-methyl-1H-pyridin-2-one-5-yl,-   2,6-dimethoxy-pyrimidin-4-yl, 2,4-dimethoxy-pyrimidin-5-yl,    4,6-dimethoxy-pyrimidin-5-yl,-   2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl,-   3,6-di methoxy-pyridazin-4-yl.

A still yet further special embodiment of the compounds of the presentinvention include those compounds of formula I, in which Har is

-   6-(imidazol-1-yl)-pyridin-3-yl, pyrimidin-5-yl,-   2-methoxy-pyrimidin-5-yl, 2-dimethylamino-pyrimidin-5-yl,    2-methylsulfanyl-pyrimidin-5-yl,-   2,6-dimethoxy-pyridin-3-yl, 4,6-dimethoxy-pyridin-3-yl,    1-methyl-1H-pyridin-2-one-5-yl,-   2,4-dimethoxy-pyrimidin-5-yl,    2-dimethylamino-4-methoxy-pyrimidin-5-yl,    1-methyl-1H-pyrimidin-2-one-5-yl, or 3,6-dimethoxy-pyridazin-4-yl.

Suitable compounds according to the present invention more worthy to bementioned include those compounds of formula I, in which R5 or,particularly, R4 is hydroxyl.

Exemplary compounds according to the present invention may include,without being restricted thereto, compounds selected from the groupconsisting of those compounds mentioned in the following examples asfinal compounds, particularly those embodimental examples which are fromformula I according to embodiment a, in which R3, R31, R41 and R5 areall hydrogen, and/or those compounds listed in the Table A in theappended “Biological Investigations”, the enantiomers, as well as thesalts, the N-oxides and the salts of the N-oxides of these compounds andenantiomers.

Preferably, any or all of those compounds of formula I according toembodiment a, in which R3, R31, R41 and R5 are all hydrogen, which aredescribed by way of example as final compounds in the following examplesand, particularly, the enantiomers thereof, particularly those havingthe formula Ia*****, as well as the salts of these compounds andenantiomers, are to be mentioned as a particular interesting aspect ofthe present invention.

The compounds of formula I are chiral compounds having chiral centers atleast in positions 4a and 10b and depending on the meanings of R3, R31,R4 and R5 additional chiral centers in positions 1, 2, 3 and 4.

The invention includes all conceivable stereoisomers in pure form aswell as in any mixing ratio. Preference is given to compounds of formulaI in which the hydrogen atoms in positions 4a and 10b are in the cisposition relative to one another. The pure cis enantiomers and theirmixtures in any mixing ratio and including the racemates are morepreferred in this context.

Particularly preferred in this context are those compounds of formula I,which have with respect to the positions 4a and 10b the configurationshown in formula (I*):

If, for example, in compounds of formula I* R3, R31 and R5 have themeaning hydrogen and R4 has the meaning —OR41, then theconfiguration—according to the rules of Cahn, Ingold and Prelog—is R inthe 4a position and R in the 10b position.

Further preferred compounds of the formula I according to embodiment aare those which have, with respect to the positions 2, 4a and 10b, thesame configuration as shown in the formulae Ia** and Ia*** and Ia****:

If, for example in compounds of the formula Ia** R3, R31 and R5 have themeaning hydrogen, then the configuration—according the rules of Cahn,Ingold and Prelog—is S in the position 2, R in the position 4a and R inthe position 10b.

If for example in compounds of the formula Ia*** R3, R31 and R5 have themeaning hydrogen, then the configuration—according the rules of Cahn,Ingold and Prelog—is R in the position 2, S in the position 4a and S inthe position 10b.

If, for example in compounds of the formula Ia**** R3, R31 and R5 havethe meaning hydrogen, then the configuration—according the rules ofCahn, Ingold and Prelog—is S in the position 2, S in the position 4a andS in the position 10b.

In more particular preferred compounds of the formula I accordingembodiment a are those which have, with respect to the positions 2, 4aand 10b, the same configuration as shown in the formula Ia*****:

If, for example in compounds of the formula Ia***** R3, R31 and R5 havethe meaning hydrogen, then the configuration—according the rules ofCahn, Ingold and Prelog—is R in the position 2, R in the position 4a andR in the position 10b.

Preferred compounds of the formula I according to embodiment b are thosewhich have, with respect to the positions 3, 4a and 10b, the sameconfiguration as shown in the formulae Ib** and Ib*** and Ib****:

If, for example in compounds of the formula Ib** R3, R31 and R5 have themeaning hydrogen, then the configuration—according the rules of Cahn,Ingold and Prelog—is R in the position 3, R in the position 4a and R inthe position 10b.

If, for example in compounds of the formula Ib*** R3, R31 and R6 havethe meaning hydrogen, then the configuration—according the rules ofCahn, Ingold and Prelog—is S in the position 3, S in the position 4a andS in the position 10b.

If, for example in compounds of the formula Ib*** R3, R31 and R5 havethe meaning hydrogen, then the configuration—according the rules ofCahn, Ingold and Prelog—is R in the position 3, S in the position 4a andS in the position 10b.

More preferred compounds of the formula I according to embodiment b arethose which have, with respect to the positions 3, 4a and 10b, the sameconfiguration as shown in the formula Ib*****:

If, for example in compounds of the formula Ib***** R3, R31 and R5 havethe meaning hydrogen, then the configuration—according the rules ofCahn, Ingold and Prelog—is S in the position 3, R in the position 4a andR in the position 10b.

Within the meaning of the embodiments a and b according to thisinvention, compounds of formula Ia***** are in particular to beemphasized.

The enantiomers can be separated in a manner known per se (for exampleby preparation and separation of appropriate diastereoisomericcompounds). Thus, e.g. an enantiomer separation can be carried out atthe stage of the starting compounds having a free amino group such asstarting compounds of formulae IVa or VIIb as defined below.

Separation of the enantiomers can be carried out, for example, by meansof salt formation of the racemic compounds of the formulae IVa or VIIbwith optically active acids, preferably carboxylic acids, subsequentresolution of the salts and release of the desired compound from thesalt. Examples of optically active carboxylic acids which may bementioned in this connection are the enantiomeric forms of mandelicacid, tartaric acid, O,O′-dibenzoyltartaric acid, camphoric acid, quinicacid, glutamic acid, pyroglutamic acid, malic acid, camphorsulfonicacid, 3-bromocamphorsulfonic acid, α-methoxyphenylacetic acid,α-methoxy-α-trifluoromethylphenylacetic acid and 2-phenylpropionic acid.Alternatively, enantiomerically pure starting compounds of the formulaeIVa or VIIb can be prepared via asymmetric syntheses. Enantiomericallypure starting compounds as well as enantiomerically pure compounds ofthe formula I can be also obtained by chromatographic separation onchiral separating columns; by derivatization with chiral auxiliaryreagents, subsequent diastereomer separation and removal of the chiralauxiliary group; or by (fractional) crystallization from a suitablesolvent.

The compounds according to the invention can be prepared, for example,as shown in the reaction schemes below and according to the followingspecified reaction steps, or, particularly, in a manner as described byway of example in the following examples, or analogously or similarlythereto according to preparation procedures or synthesis strategiesknown to the person skilled in the art.

Compounds of formula I, in which R1, R2, R3, R31, R4, R5 and Har havethe meanings mentioned above, according to embodiment a or b (i.e.compounds of formulae Ia or Ib, respectively) can be obtained asdescribed as follows.

Compounds of formula Ia according to embodiment a, in which R1, R2, R3,R31, R41, R5 and Har have the meanings mentioned above in embodiment awhereby R41 is other than hydrogen, can be prepared as described andshown in reaction scheme 1 below.

In the first reaction step of the synthesis route shown in scheme 1,compounds of the formula Va, in which R1, R2, R3, R31, R41 and R5 havethe meanings mentioned above in embodiment a whereby R41 is other thanhydrogen, are prepared from the corresponding compounds of the formulaVIa by introduction of the group R41 whereby R41 is other than hydrogen.The introduction reaction is carried out in a manner habitual per se foran etherification or esterification reaction, or as described by way ofexample in the following examples.

In the next reaction step of the synthesis route shown in reactionscheme 1, the nitro group of compounds of the formula Va, in which R1,R2, R3, R31, R41 and R5 have the meanings mentioned above in embodimenta whereby R41 is other than hydrogen, is reduced to the amino group ofthe corresponding compounds of the formula IVa. Said reduction iscarried out in a manner known to the person skilled in the art, forexample as described in J. Org. Chem. 1962, 27, 4426 or as described inthe following examples. In more detail, the reduction can be carriedout, for example, by catalytic hydrogenation, e.g. in the presence ofRaney nickel or a noble metal catalyst such as palladium on activecarbon, in a suitable solvent such as methanol or ethanol at roomtemperature and under normal or elevated pressure. Optionally, acatalytic amount of an acid, such as, for example, hydrochloric acid,can be added to the solvent. Preferably, however, the reduction iscarried out using a hydrogen-producing mixture, for example, metals suchas zinc, zinc-copper couple or iron with organic acids such as aceticacid or mineral acids such as hydrochloric acid. More preferably, thereduction is carried out using a zinc-copper couple in the presence ofan organic or an inorganic acid. Such a zinc-copper couple is accessiblein a way known to the person of ordinary skill in the art.

Compounds of the formula IVa, in which R1, R2, R3, R31, R41 and R5 havethe meanings indicated above in embodiment a whereby R41 is other thanhydrogen and which are sensitive against catalytic hydrogenation, can beprepared from the corresponding compounds of the formula Va by selectivereduction of the nitro group in a manner known to the person skilled inthe art, for example by hydrogen transfer reaction in the presence of ametal catalyst, for example palladium or, preferably, Raney nickel, in alower alcohol as solvent using, for example, ammonium formiate or,preferably, hydrazine hydrate as hydrogen donor.

Compounds of the formula IIa, in which R1, R2, R3, R31, R41, R5 and Harhave the meanings indicated above in embodiment a whereby R41 is otherthan hydrogen, are accessible from the corresponding compounds of theformula IVa by reaction with corresponding compounds of the formula III,in which X represents a suitable leaving group, preferably a chlorineatom.

Alternatively, compounds of the formula IIa can also be prepared fromthe corresponding compounds of the formula IVa and correspondingcompounds of the formula III, in which X is hydroxyl, by reaction withamide bond linking reagents known to the person skilled in the art.Exemplary amide bond linking reagents known to the person skilled in theart which may be mentioned are, for example, the carbodiimides (e.g.dicyclohexylcarbodiimide or, preferably,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride),azodicarboxylic acid derivatives (e.g. diethyl azodicarboxylate),uronium salts [e.g. O-(benzotriazol-1-yl)-N, N,N′,N′-tetramethyluroniumtetrafluoroborate orO-(benzotriazol-1yl)-N,N,N′,N′-tetramthyl-uronium-hexafluorophosphate]and N,N′-carbonyldiimidazole. In the scope of this invention preferredamide bond linking reagents are uronium salts and, particularly,carbodiimides, preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride.

Compounds of the formula III are either known or can be prepared in aknown manner.

Compounds of the formula Ia, in which R1, R2, R3, R31, R41, R5 and Harhave the meanings mentioned in embodiment a whereby R41 is other thanhydrogen, can be obtained by cyclocondensation of correspondingcompounds of the formula IIa.

Said cyclocondensation reaction is carried out in a manner known per seto the person skilled in the art or as described by way of example inthe following examples, according to Bischler-Napieralski (e.g. asdescribed in J. Chem. Soc., 1956, 4280-4282) in the presence of asuitable condensing agent, such as, for example, polyphosphoric acid,phosphorus pentachioride, phosphorus pentoxide or phosphorusoxychloride, in a suitable inert solvent, e.g. in a chlorinatedhydrocarbon such as chloroform, or in a cyclic hydrocarbon such astoluene or xylene, or another inert solvent such as isopropyl acetate oracetonitrile, or without further solvent using an excess of condensingagent, at reduced temperature, or at room temperature, or at elevatedtemperature or at the boiling temperature of the solvent or condensingagent used. If necessary, said cyclocondensation reaction can be carriedout in the presence of one or more suitable Lewis Acids such as, forexample, suitable metal halogenides (e.g. chlorides) or sulphonates(e.g. triflates), including rare earth metal salts, such as e.g.anhydrous aluminum tri-chloride, aluminum tribromide, zinc chloride,boron trifluoride ethereate, titanium tetrachloride or, in particular,tin tetrachloride, and the like.

Parallel to the cyclization in the presence of a chlorine-containingcondensing agent (such as e.g. phosphorus pentachloride), a nucleophilicor electrophilic substitution of the Har moiety giving the correspondingchlorine substituted Har moiety can take place, especially in the caseof electron rich Har groups, such as e.g. the dimethoxypyridinylradical, like the 2,6-dimethoxypyridin-4-yl or the2,6-dimethoxy-pyridin-3-yl radical, an electrophilic substitution cantake place, and especially in the case of Har radicals incorporatingcyclic amide structures (e.g. NH-pyridones or NH-pyrimidones) anucleophilic substitution of the oxo group can take place.

Below reaction scheme 2 shows the synthesis of compounds of the formulaVIa, in which R1, R2, R3, R31 and R5 have the meanings indicated abovein embodiment a, from corresponding compounds of the formula VIIa viareduction reaction of the carbonyl group. Suitable reducing agents forthe abovementioned reduction reaction may include, for example, metalhydride compounds such as, for example, diisopropylaluminium hydride,borane, sodium borohydride, sodium triacetoxyborohydride, sodiumcyanoborohydride, zinc borohydride, potassium tri-sec-butylborohydride,sodium tri-sec-butylborohydride, lithium td-sec-butylborohydride,β-isopinocampheyl-9-borabicyclo[3.3.1]nonane and the like. The preferredexamples of said reducing agents are sodium cyanoborohydride,3-isopinocampheyl-9-borabicyclo[3.3.1]nonane and potassiumtri-sec-butylborohydride. The most preferred examples of theabovementioned reducing agents arep-isopinocampheyl-9-borabicyclo[3.3.1]nonane and potassiumtri-sec-butylborohydride, which both allow to prepare compounds of theformula VIa stereoselectively. “Stereoselectively” in this connectionmeans that those compounds of the formula VIa, in which the hydrogenatoms in positions 1 and 3 are located at the opposite side of the planedefined by the cyclohexane ring, are obtained preferentially.

The compounds of the formula VIIa, in which R1, R2, R3, R31 and R5 havethe meanings mentioned in embodiment a, are either known or can beobtained by the reaction of compounds of the formula IXa, in which R1and R2 have the meanings mentioned above, with compounds of the formulaVIIIa, in which R3, R31 and R5 have the meanings mentioned above inembodiment a. The cycloaddition reaction is carried out in a mannerknown to the person skilled in the art according to Diels-Alder, e.g. asdescribed in J. Amer. Chem. Soc. 1957, 79, 6559 or in J. Org. Chem.1952, 17, 581 or as described in the following examples.

Compounds of the formulae VIa or Va, in which the phenyl ring and thenitro group are trans to one another, can be converted in a manner knownto the person skilled in the art into the corresponding cis compounds,e.g. as described in J. Amer. Chem. Soc. 1957, 79, 6559 or as describedin the following examples.

The compounds of the formulae VIIIa and IXa are either known or can beprepared in a known manner. The compounds of the formula IXa can beprepared, for example, in a manner known to the person skilled in theart from corresponding compounds of the formula Xa as described, forexample, in J. Chem. Soc. 1951, 2524 or in J. Org. Chem. 1944, 9, 170 oras described in the following examples.

The compounds of the formula Xa, in which R1 and R2 have the meaningsindicated above in embodiment a, are either known or can be prepared ina manner known to the person skilled in the art, as described, forexample, in Ber. Dtsch. Chem. Ges. 1925, 58, 203.

Compounds of formula Ib according to embodiment b, in which R1, R2, R3,R31, R4, R51 and Har have the meanings indicated above in embodiment bwhereby R51 is other than hydrogen, can be prepared as described andshown in reaction scheme 3 below.

In the first reaction step in reaction scheme 3, the nitro group ofcompounds of the formula VIIIb, in which R1, R2, R3, R31 and R4 have themeanings indicated in embodiment b above, is reduced to obtaincorresponding compounds of the formula VIIb. Said reduction reaction iscarried out in a manner known to the person skilled in the art, forexample as described in J. Org. Chem. 1962, 27, 4426 or as described inthe following examples. More specifically, the reduction can be carriedout, for example, by contacting compounds of the formula VIIIb with ahydrogen-producing mixture such as, preferably, metallic zinc in amildly acidic medium such as acetic acid in a lower alcohol such asmethanol or ethanol at room temperature or at elevated temperature or,preferably, at the boiling temperature of the solvent mixture.Alternatively, the reduction can be carried out by selective reductionof the nitro group in a manner known to the person skilled in the art,for example by hydrogen transfer reaction in the presence of a metalcatalyst, for example palladium or preferably Raney nickel, in asuitable solvent, preferably a lower alcohol, using, for exampleammonium formiate or preferably hydrazine hydrate as hydrogen donor.

Compounds of the formula VIIb obtained can be reacted, for example, asdescribed by way of example in the following examples with compounds ofthe formula III, in which R6 and R7 have the meanings given above and Xrepresents a suitable leaving group, preferably a chlorine atom, to givecorresponding compounds of the formula VIb.

Alternatively, compounds of the formula VIb, in which R1, R2, R3, R31,R4 and Har have the meanings given above in embodiment b, can also beprepared, for example, from corresponding compounds of the formula VIIband corresponding compounds of the formula III, in which X is hydroxyl,by reaction with amide bond linking reagents known to the person skilledin the art. Exemplary amide bond linking reagents known to the personskilled in the art which may be mentioned are, for example, thecarbodiimides (e.g. dicyclohexylcarbodiimide or, preferably,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride),azodicarboxylic acid derivatives (e.g. diethyl azodicarboxylate),uronium salts [e.g. O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate orO-(benzotriazol-1yl)-N,N,N′,N′-tetramthyl-uroriium-hexafluorophosphate]and N,N′-carbonyldiimidazole. In the scope of this invention preferredamide bond linking reagents are uronium salts and, particularly,carbodiimides, preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride.

In the next step compounds of the formula VIb are converted intocorresponding compounds of the formula Vb by epoxidation reaction, whichcan be carried out as described in the following examples or in a mannerknown to one of ordinary skill in the art employing, for example,suitable epoxidation methods or suitable epoxidation reagents such as,for example, peracids (e.g. m-chloroperbenzoic acid) or organic orinorganic peroxides (e. g. dimethyldioxirane, hydrogene peroxide orpersulfates).

Compounds of the formula Vb obtained can be reduced by art-known methodsto corresponding compounds of the formula IVb. More specifically, saidreduction reaction can be performed employing, for example, as describedby way of example in the following examples sodium borohydride asreductant. Alternatively, said reduction reaction can be also carriedout using, for example, lithium aluminium hydride or a reductive mixturecomprising noble metals, such as platinium dioxide or palladium, and asuitable hydrogen donor. With the aid of each of those said reductionmethods, compounds of the formula Vb can be converted largely regio- anddiastereoselectively into compounds of the formula IVb, wherein thehydroxyl radical in position 1 and the amido radical in position 3 arelocated at the same side of the plane defined by the cyclohexane ring.

It is moreover known to one of ordinary skill of the art, that theabsolute configuration of a chiral carbon atom, preferably, to which ahydroxyl group and a hydrogen atom are bonded, can be inverted. Thus theconfiguration of the carbon atom in position 1 of compounds of theformula IVb can be optionally inverted. Said inversion of configurationof position 1 of compounds of the formula IVb can be achieved in amanner familiar to the person skilled in the art, for example byderivatization of position 1 with a suitable leaving group andsubsequent replacement of said leaving group by a suitable nucleophilein a nucleophilic substitution reaction according to SN2 mechanism.Alternatively, said inversion of configuration of position 1 ofcompounds of the formula IVb can be also obtained, for example, asdescribed by Way of example in the following examples according tosubsequently specified two step procedure shown in reaction scheme 4below. In more detail, in the first step of said procedure shown inreaction scheme 4, exemplary compounds of the formula IVb*, in which R1,R2 and Har have the meanings indicated above in embodiment b, and R3,R31 and R4 are hydrogen and position 1 has the R configuration, areconverted by oxidation reaction into corresponding compounds of theformula IXb. Said oxidation is likewise carried out under conditionscustomary per se using, for example, chloranil, atmospheric oxygen,manganese dioxide or, preferably, chromium oxides as an oxidant. Then inthe second step, compounds of the formula IXb obtained are converted byart-known reduction reaction of the keto group, preferably with metalhydride compounds or, more specifically, metal borohydrides, such as,for example, sodium borohydride, into corresponding compounds of formulaIVb**, in which position 1 has now S configuration and thus theconfiguration of the carbon atom in position 1 is now inverted regardingto said compounds of the formula IVb*.

In the next reaction step of the synthesis route shown in reactionscheme 3 shown above, compounds of the formula IVb are converted intocorresponding compounds of the formula IIb by introduction of the groupR51 whereby R61 is other than hydrogen. The introduction reaction iscarried out in a manner habitual per se (e.g. via alkylation oracylation reaction) or as described by way of example in the followingexamples.

The cyclization reaction leading to compounds of the formula Ib, inwhich R1, R2, R3, R31, R4, R51 and Har have the meanings given above inembodiment b whereby R51 is other than hydrogen, can be carried out, forexample, as described by way of example in the following examples oranalogously or similarly thereto, or as mentioned above for compoundsaccording to embodiment a.

Compounds of the formula VIIIb, in which R1, R2, R3, R31 and R4 have themeanings mentioned above in embodiment b, are either known or can beobtained, for example as shown in reaction scheme 5, by the reaction ofcompounds of the formula IXa, in which R1 and R2 have the abovementionedmeanings, with compounds of the formula Xb, in which R3, R31 and R4 havethe meanings indicated above in embodiment b.

The cycloaddition is in this case carried out in a manner known to theperson skilled in the art according to Diels-Alder, e.g. as described inJ. Amer. Chem. Soc. 1957, 79, 6559 or in J. Org. Chem. 1952, 17, 581 oras described in the following examples.

Compounds of the formula VIIIb, in which the phenyl ring and the nitrogroup are trans to one another, can be converted such as known to theperson skilled in the art into the corresponding cis compounds, e.g. asdescribed in J. Amer. Chem. Soc. 1957, 79, 6559 or as described in thefollowing examples.

The compounds of the formula Xb are either known or can be prepared in aknown manner.

In an alternative, compounds of the formula IIb, in which R1, R2, R3,R31, R4, R51 and Har have the meanings given above in embodiment bwhereby R51 is other than hydrogen (particularly compounds of formulaIIb, in which R1, R2 and R51 have the meanings given above in embodimentb whereby R51 is other than hydrogen, and R3, R31 and R4 are allhydrogen) can also be obtained as shown in reaction scheme 6 and asdescribed by way of example in the following examples.

In the first reaction step of the route outlined in reaction scheme 6,the amino group of compounds of the formula VIIb is protected with anart-known protective group PG1, such as e.g. the tert-butoxycarbonylgroup. The protected compounds are subjected to hydroboration reactionto obtain over two steps compounds of formula XIb. Said hydroborationreaction is carried out as described in the following examples using anappropriate (hydro)borating agent, such as e.g. 9-BBN,isopinocampheyl-borane or the like, or, particularly,borane-tetrahydrofuran (H₃B-THF), advantageously at ambient temperature.

The compounds obtained are then converted into compounds of the formulaXIb by introduction of the group R51 whereby R51 is other than hydrogenin a manner analogously as described above.

In the next reaction step of the synthesis route shown in reactionscheme 6, compounds of formula XIb are converted into correspondingcompounds of the formula IIb by deprotection of the protective group PG1and amidification with compounds of the formula III. Said reactions arecarried out in a manner habitual per se or as described in thespecification of this invention or in the following examples.

If necessary, the product obtained via said hydroboration reaction or,suitably, the R51-substituted de-rivative thereof is purified fromresulting stereo- and/or regioisomeric side products by methods known tothe person skilled in the art, such as e.g. by chromatographicseparation techniques.

Optionally, compounds of the formula I can be also converted intofurther compounds of the formula I by methods known to one of ordinaryskill in the art. More specifically, for example, from compounds of theformula I in which

-   a) R41 or R51 is hydrogen, the corresponding ester compounds can be    obtained by esterification reactions;-   b) R41 or R51 is hydrogen, the corresponding ether compounds can be    obtained by etherification reactions;-   c) R41 or R51 is an acyl group, such as e.g. acetyl, the    corresponding hydroxyl compounds can be obtained by deesterification    (e.g. saponification) reactions;-   d) R6 and/or R7 is chlorine, further compounds of formula I can be    obtained via nucleophilic substitution reactions with N, S or O    nucleophiles;-   e) R6 is an ester group, the corresponding carboxylic acid can be    obtained via saponification-   f) R6 is a cyano group, the corresponding ester compounds can be    obtained via alcoholysis and then hydrolysis, e.g. in acid medium,    of the resulting intermediate imino esters.-   g) R6 is a cyano group, the corresponding acid compounds can be    obtained via alcoholysis and then hydrolysis, e.g. in base medium,    of the resulting intermediate imino esters.

The methods mentioned under a), b), c), d), e.), f.) and g.) areexpediently carried out analogously to the methods known to the personskilled in the art or as described by way of example in the followingexamples.

Optionally, compounds of the formula I can be converted into theirsalts, or, optionally, salts of the compounds of the formula I can beconverted into the free compounds.

In addition, the compounds of the formula I can be converted,optionally, into their N-oxides, for example with the aid of hydrogenperoxide in methanol or with the aid of m-chloroperoxybenzoic acid indichloromethane. The person skilled in the art is familiar on the basisof his/her expert knowledge with the reaction conditions which arespecifically necessary for carrying out the N-oxidation.

It is moreover known to the person skilled in the art that if there area number of reactive centers on a starting or intermediate compound itmay be necessary to block one or more reactive centers tempo-rarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in“Protective Groups in Organic Synthesis” by T. Greene and P. Wuts (JohnWiley & Sons, Inc. 1999, 3^(rd) Ed.) or in “Protecting Groups (ThiemeFoundations Organic Chemistry Series N Group” by P. Kocienski (ThiemeMedical Publishers, 2000).

The substances according to the invention are isolated and purified in amanner known per se, for example by distilling off the solvent underreduced pressure and recrystallizing the residue obtained from asuitable solvent or subjecting it to one of the customary purificationmethods, such as, for example, column chromatography on a suitablesupport material.

Salts are obtained by dissolving the free compound in a suitable solvent(e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutylketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, achlorinated hydrocarbon, such as methylene chloride or chloroform, or alow-molecular-weight aliphatic alcohol, such as ethanol or isopropanol)which contains the desired acid or base, or to which the desired acid orbase is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted into thefree compounds, which can in turn be converted into salts, byalkalization or by aci-dification. In this manner, pharmacologicallyunacceptable salts can be converted into pharmacologically acceptablesalts.

The solvates or particularly hydrates of the compounds according to thisinvention can be prepared in a manner known per se, e.g. in the presenceof the appropriate solvent. Hydrates may be obtained from water or frommixtures of water with polar organic solvents (for example alcohols,e.g. methanol, ethanol or isopropanol, or ketones, e.g. acetone).

Suitably, the conversions mentioned in this invention can be carried outanalogously or similarly to methods which are familiar per se to theperson skilled in the art.

The person skilled in the art knows on the basis of his/her knowledgeand on the basis of those synthesis routes, which are shown anddescribed within the description of this invention, how to find otherpossible synthesis routes for compounds of the formula I. All theseother possible synthesis routes are also part of this invention.

Having described the invention in detail, the scope of the presentinvention is not limited only to those described characteristics orembodiments. As will be apparent to persons skilled in the art,modifica-tions, analogies, variations, derivations, homologisations andadaptations to the described invention can be made on the base ofart-known knowledge and/or, particularly, on the base of the disclosure(e.g. the explicite, implicite or inherent disclosure) of the presentinvention without departing from the spirit and scope of this inventionas defined by the scope of the appended claims.

The following examples serve to illustrate the invention further withoutrestricting it. Likewise, further compounds of the formula I, whosepreparation is not explicitly described, can be prepared in an analogousor similar manner or in a manner familiar per se to the person skilledin the art using customary process techniques.

Any or all of the compounds which are mentioned as final compounds inthe following examples as well as their salts, N-oxides and salts of theN-oxides are a preferred subject of the present invention.

In the examples, m.p. stands for melting point, h for hour(s), min forminutes, R_(f) for rentention factor in thin layer chromatography, s.p.for sintering point, EF for empirical formula, MW for molecular weight,MS for mass spectrum, M for molecular ion, fnd. for found, catc. forcalculated, other abbreviations have their meanings customary per se tothe skilled person.

According to common practice in stereochemistry, the symbols RS and SRare used to denote the specific configuration of each of the chiralcenters of a racemate. In more detail, for example, the term“(2RS,4aRS,10bRS)” stands for a racemate (racemic mixture) comprisingthe one enantiomer having the configuration (2R,4aR,10bR) and the otherenantiomer having the configuration (2S,4aS,10bS).

EXAMPLES

Final Compounds

1.(2RS,4aRS,10bRS)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

423 mg of acetic acid(2RS,4aRS,10bRS)-6-(2,6-dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester (Example 18) dissolved in 1 ml of dichloromethane and 9 ml ofmethanol are added to 152 mg of cesium carbonate and the solutionstirred for 19 h. The reaction mixture is adsorbed to silica gel andpurified by flash chromatography to give 229 mg of the title compound asa colourless foam.

EF: C₂₃H₂₈N₂O₅; MW: calc.: 412.49

MS: fnd.: 413.3 (MH⁺)

Starting from the appropriate ester compounds, which are mentioned ordescribed explicitly below (compounds 18 to 34), or which can beprepared in a manner known to the person skilled in the art oranalogously or similarly to the examples described herein, the followingcompounds 2 to 17, and also further relevant, non-explicitly describedsimilar compounds are obtained according to the procedure as in Example1.

2.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-(3-methyl-3H-imidazol-4-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₀H₂₅N₃O₃; MW: calc.: 355.44

MS: fnd.: 356.3 (MH⁺)

3.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-(2-pyridin-3-yl-thiazol-4-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₄H₂₅N₃O₃S; MW: calc.: 435.55

MS: fnd.: 436.2 (MH⁺)

4.(2RS,4aRS,10bRS)-9-Ethoxy-6-isoxazol-5-yl-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₁₉H₂₂N₂O₄; MW: calc.: 342.4

MS: fnd.: 343.2 (MH⁺)

5.(2RS,4aRS,10bRS)-8,9-Dimethoxy-6-pyridin-4-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₀H₂₂N₂O₃; MW: calc.: 338.41

MS: fnd.: 339.4 (MH⁺)

6.(2RS,4aRS,10bRS)-8,9-Dimethoxy-6-pyridin-3-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₀H₂₂N₂O₃; MW: calc.: 338.41

MS: fnd.: 339.3 (MH⁺)

7.(2RS,4aRS,10bRS)-8,9-Dimethoxy-6-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₄H₂₉N₃O₄; MW: calc.: 423.52

MS: fnd.: 424.4 (MH⁺)

8.(2RS,4aRS,10bRS)-6-Benzo[1,2,5]oxadiazol-5-yl-9-(1,1-difluoro-methoxy)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₁H₁₉F₂N₃O₄; MW: calc.: 415.4

MS: fnd.: 416.2 (MH⁺)

9.(2RS,4aRS,10bRS)-6-Benzo[1,2,5]oxadiazol-5-yl-9-(2,2-difluoro-ethoxy)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₂H₂₁F₂N₃O₄; MW: calc.: 429.43

MS: fnd.: 430.3 (MH⁺)

10.(2RS,4aRS,10bRS)-6-Benzo[1,2,5]oxadiazol-5-yl-8-(1,1-difluoro-methoxy)-9-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₁H₁₉F₂N₃O₄; MW: calc.: 415.4

MS: fnd.: 416.3 (MH⁺)

11.(2RS,4aRS,10bRS)-6-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-01

EF: C₂₄H₂₇NO₅; MW: calc.: 409.49

MS: fnd.: 410.3 (MH⁺)

12.(2RS,4aRS,10bRS)-6-Benzo[1,3]dioxol-5-yl-9-ethoxy-8-methoxy-1,2,3,4,4a,1b-hexahydro-phenanthridin-2-ol

EF: C₂₃H₂₅NO₅; MW: calc.: 395.46

MS: fnd.: 396.2 (MH⁺)

13.(2RS,4aRS,10bRS)-6-Benzothiazol-6-yl-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₃H₂₄N₂O₃S; MW: calc.: 408.52

MS: fnd.: 409.2 (MH⁺)

14.(2RS,4aRS,10bRS)-8,9-Dimethoxy-6-quinolin-6-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₄H₂₄N₂O₃; MW: calc.: 388.47

MS: fnd.: 389.4 (MH⁺)

15.(2RS,4aRS,10bRS)-6-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₂H₂₁F₂NO₅; MW: calc.: 417.41

MS: fnd.: 418.4 (MH⁺)

16.(2RS,4aRS,10bRS)-6-Benzo[1,2,5]oxadiazol-5-yl-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

EF: C₂₂H₂₃N₃O₄; MW: calc.: 393.45

MS: fnd.: 394.3 (MH⁺)

17.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-(1-methyl-1H-Imidazol-2-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol18. Acetic acid(2RS,4aRS,10bRS)-6-(2,6-dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

1.67 g of phosphorus pentachioride are suspended in 5 ml ofdichloromethane. 1.227 g of crude acetic acid(1RS,3RS,4RS)-4-{[1-(2,6-dimethoxy-pyridin-3-yl)methanoyl]amino}-3-(3-ethoxy-4-methoxyphenyl)cyclohexylester (compound A1) dissolved in 15 ml of dichloromethane are added andthe reaction mixture stirred at room temperature over night. Thereaction mixture is cooled with an ice bath and 20 ml of triethylamineare added, than cautiously 10 ml of water with vigorous stirring. Theorganic layer is separated, concentrated and the crude product purifiedby flash chromatography to give 715 mg of the title compound.

EF: C₂₅H₃₀N₂O₆; MW: calc.: 454.53

MS: fnd.: 455.2 (MH⁺)

Starting from the appropriate starting compounds, which are mentioned ordescribed explicitly below (compounds A2 to A17), or which can beprepared in a manner known to the person skilled in the art oranalogously or similarly to the examples described herein, the followingcompounds 19 to 34, and also further relevant, non-explicitly describedsimilar compounds are obtained according to the procedure as in Example18. If necessary, the cyclization reaction can be carried out in thepresence of a catalytic amount of a Lewis acid such e.g. tintetrachloride.

19. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-(3-methyl-3H-imidazol-4-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₂H₂₇N₃O₄; MW: calc.: 397.48

MS: fnd.: 398.2 (MH⁺)

20. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-(2-pyridin-3-yl-thiazol-4-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₆H₂₇N₃O₄S; MW: calc.: 477.59

MS: fnd.: 478.2 (MH⁺)

21. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-6-isoxazol-5-yl-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₁H₂₄N₂O₅; MW: calc.: 384.44

MS: fnd.: 385.2 (MH⁺)

22. Acetic acid(2RS,4aRS,10bRS)-8,9-dimethoxy-6-pyridin-4-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₂H₂₄N₂O₄; MW: calc.: 380.45

MS: fnd.: 381.3 (MH⁺)

23. Acetic acid(2RS,4aRS,10bRS)-8,9-dimethoxy-6-pyridin-3-yl-1,2,3,4,4a,1b-hexahydro-phenanthridin-2-yl ester

EF: C₂₂H₂₄N₂O₄; MW: calc.: 380.45

MS: fnd.: 381.3 (MH⁺)

24. Acetic acid(2RS,4aRS,10bRS)-8,9-dimethoxy-6-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4,4a,1b-hexahydro-phenanthridin-2-yl ester

EF: C₂₆H₃₁N₃O₅; MW: calc.: 465.44

MS: fnd.: 466.4 (MH⁺)

25. Acetic acid(2RS,4aRS,10bRS)-6-benzo[1,2,5]oxadiazol-5-yl-9-(1,1-difluoro-methoxy)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₃H₂₁F₂N₃O₅; MW: calc.: 457.44

MS: fnd.: 458.2 (MH⁺)

26. Acetic acid(2RS,4aRS,10bRS)-6-benzo[1,2,5]oxadiazol-5-yl-9-(2,2-difluoro-ethoxy)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₄H₂₃F₂N₃O₅; MW: calc.: 471.46

MS: fnd.: 472.2 (MH⁺)

27. Acetic acid(2RS,4aRS,10bRS)-6-benzo[1,2,5]oxadiazol-5-yl-8-(1,1-difluoro-methoxy)-9-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₃H₂₁F₂N₃O₃; MW: calc.: 457.44

MS: fnd.: 458.2 (MH⁺)

28. Acetic acid(2RS,4aRS,10bRS)-6-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,1b-hexahydro-phenanthridin-2-yl ester

EF: C₂₆H₂₉F₂NO₆; MW: calc.: 451.52

MS: fnd.: 452.3 (MH⁺)

29. Acetic acid(2RS,4aRS,10bRS)-6-benzo[1,3]dioxol-5-yl-9-ethoxy-8-methoxy-1,2,3,4,4a,1b-hexahydro-phenanthridin-2-ylester

EF: C₂₅H₂₇NO₆; MW: calc.: 437.5

MS: fnd.: 438.2 (MH⁺)

30. Acetic acid(2RS,4aRS,10bRS)-6-benzothiazol-6-yl-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₅H₂₆N₂O₄S; MW: calc.: 450.56

MS: fnd.: 451.2 (MH⁺)

31. Acetic acid(2RS,4aRS,10bRS)-8,9-dimethoxy-6-quinolin-6-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₆H₂₆N₂O₄; MW: calc.: 430.51

MS: fnd.: 431.3 (MH⁺)

32. Acetic acid(2RS,4aRS,10bRS)-6-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₄H₂₃F₂NO₆; MW: calc.: 459.48

MS: fnd.: 460.3 (MH⁺)

33. Acetic acid(2RS,4aRS,10bRS)-6-benzo[1,2,5]oxadiazol-5-yl-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₄H₂₅N₃O₅; MW: calc.: 435.48

MS: fnd.: 436.3 (MH⁺)

34. Acetic acid (2 RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-(1-methyl-1H-imidazol-2-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₂H₂₇N₃O₄; MW: calc.: 397.48

MS: fnd.: 398.2 (MH⁺)

35.5-((2RS,4aRS,10bRS)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboxylicacid methyl ester

532 mg of acetic acid(2RS,4aRS,10bRS)-6-(6-cyano-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester (compound 44) and 248 mg of cesium carbonate are stirred in 10 mlof methanol (optionally 2 ml of dichloromethane can be added) for 19 h.The solvent is removed and the residue purified by chromatography togive 434 mg of the corresponding imino ester (mass calc. 409.49. foundMH⁺410.3).

183 mg of the imino ester are dissolved in 15 ml of 1 M HCl and stirredfor 5 h. Na₂HPO₄ is added (pH=10-11) and extracted with dichloromethane.After drying (Na₂SO₄) the solvent is removed to give 161 mg of the titlecompound as a colorless foam.

EF: C₂₃H₂₆N₂O₅; MW: calc.: 410.47

MS: fnd.: 411.3

36.(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-6-(2,6-dimethoxy-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 45 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₃H₂₆F₂N₂O₅; MW: calc.: 448.47

MS: fnd.: 449.3

37.(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-8-methoxy-6-(2-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 46 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₂H₂₄F₂N₂O₄; MW: calc.: 418.44

MS: fnd.: 419.2

38.(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-8-methoxy-6-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-01

Starting from compound 47 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₅H₂₉F₂N₃O₄; MW: calc.: 473.52

MS: fnd.: 474.3

39.(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-8-methoxy-6-pyridin-3-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 48 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₁H₂₂F₂N₂O₃; MW: calc.: 388.42

MS: fnd.: 389.3

40.(2RS,4aRS,10bRS)-9-(2,2-Difluoro-ethoxy)-6-(2,6-dimethoxy-pyrimidin-4-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 49 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₂H₂₅F₂N₃O₅; MW: calc.: 449.46

MS: fnd.: 450.2

41.(2RS,4aRS,1013RS)-8-(2,2-Difluoro-ethoxy)-6-(2,6-dimethoxy-pyridin-3-yl)-9-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 50 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₃H₂₆F₂N₂O₅; MW: calc.: 448.47

MS: fnd.: 449.3

42.(2RS,4aRS,10bRS)-6-(2,6-Dimethoxy-pyridin-3-yl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 51 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₂H₂₆N₂O₅; MW: calc.: 398.46

MS: fnd.: 399.4

43.(2RS,4aRS,10bRS)-6-(2,6-Dimethoxy-pyridin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 52 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₃H₂₈N₂O₅; MW: calc.: 412.49 MS: fnd.: 413.2

Starting from the corresponding starting compounds, which are mentionedor described explicitly below (compounds A18 to A26), the followingcompounds 44 to 52 are obtained according to the procedure as in Example18. If necessary, the cyclization reaction can be carried out in thepresence of a catalytic amount of a Lewis acid such e.g. tintetrachloride.

44. Acetic acid(2RS,4aRS,10bRS)-6-(6-cyano-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₄H₂₅N₃O₄; MW: calc.: 419.48

45. Acetic acid(2RS,4aRS,10bRS)-9-(2,2-difluoro-ethoxy)-6-(2,6-dimethoxy-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₅H₂₈F₂N₂O₆; MW: calc.: 490.51

MS: fnd.: 491.2

46. Acetic acid(2RS,4aRS,10bRS)-9-(2,2-difluoro-ethoxy)-8-methoxy-6-(2-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₄H₂₆F₂N₂O₅; MW: calc.: 460.48

MS: fnd.: 461.2

47. Acetic acid(2RS,4aRS,10bRS)-9-(2,2-difluoro-ethoxy)-8-methoxy-6-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₇H₃₁F₂N₃O₅; MW: calc.: 516.56

48. Acetic acid(2RS,4aRS,10bRS)-9-(2,2-difluoro-ethoxy)-8-methoxy-6-pyridin-3-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₃H₂₄F₂N₂O₄; MW: calc.: 430.46

MS: fnd.: 431.3

49. Acetic acid(2RS,4aRS,10bRS)-9-(2,2-difluoro-ethoxy)-6-(2,6-dimethoxy-pyrimidin-4-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₄H₂₇F₂N₃O₆; MW: calc.: 491.50

MS: fnd.: 492.2

50. Acetic acid(2RS,4aRS,10bRS)-8-(2,2-difluoro-ethoxy)-6-(2,6-dimethoxy-pyridin-3-yl)-9-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₅H₂₈F₂N₂O₆; MW: calc.: 490.51

MS: fnd.: 431.3

51. Acetic acid(2RS,4aRS,10bRS)-6-(2,6-dimethoxy-pyridin-3-yl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₄H₂₈N₂O₆; MW: calc.: 440.5

MS: fnd.: 441.3

52. Acetic acid(2RS,4aRS,10bRS)-6-(2,6-dimethoxy-pyridin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₅H₃₀N₂O₆; MW: calc.: 454.53

MS: fnd.: 455.2

53. (2RS,4a RS, 10b RS)-6-(3-Chloro-2,6-dmethoxy-pyridn-4-yl)-9-(2,2-difluoro-ethoxy)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 54 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₃H₂₅Cl F₂N₂O₅; MW: calc.: 482.92

MS: fnd.: 483.2/485.2

54. Acetic acid(2RS,4aRS,10bRS)-6-(3-chloro-2,6-dimethoxy-pyridin-4-yl)-9-(2,2-difluoro-ethoxy)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

Starting from compound A27 the title compound is obtained according tothe procedure as in Example 18. If necessary, the cyclization reactioncan be carried out in the presence of a catalytic amount of a Lewis acidsuch e.g. tin tetrachloride.

EF: C₂₅H₂₇Cl F₂N₂O₆; MW: calc.: 524.95

MS: fnd.: 525.3

55.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-01

Starting from compound 68 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₀H₂₃N₃O₃; MW: calc.: 353.42

MS: fnd.: 354.3

56. (2R,4a R,10bR)-9-Ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 69 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₄H₂₆N₄O₃; MW: calc.: 418.5

MS: fnd.: 419.4

[α]²⁰ _(D)=−84°

57.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 70 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₆H₃₃N₃O₃; MW: calc.: 435.57

MS: fnd.: 436.4

58.6-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-nicotinicacid methyl ester

Starting from compound 71 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₃H₂₆N₂O₅; MW: calc.: 410.47

MS: fnd.: 411.3

[α]²⁰ _(D)=−82°

59.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 72 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₁H₂₅N₃O₄; MW: calc.: 383.45

MS: fnd.: 384.3

60.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2,4,6-trimethoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 73 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₃H₂₉N₃O₆; MW: calc.: 443.5

MS: fnd.: 444.3

61.(2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 74 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C_(n)H₂₇N₃O₅; MW: calc.: 413.48

MS: fnd.: 414.3

62.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(5-methyl-pyrazin-2-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 75 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₁H₂₅N₃O₃; MW: calc.: 367.45

MS: fnd.: 368.3

63.(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyrimidin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 76 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₂H₂₇N₃O₅; MW: calc.: 413.48

MS: fnd.: 414.3

[α]²⁰ _(D)=−57°.

64.(2R,4aR,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 77 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₄H₂₆N₄O₃; MW: calc.: 418.5

MS: fnd.: 419.3

65.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 78 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₀H₂₃N₃O₃; MW: calc.: 353.42

MS: fnd.: 354.3

66.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(1-methyl-1H-benzotriazol-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 79 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₃H₂₆N₄O₃; MW: calc.: 406.49

MS: fnd.: 407.2

[α]²⁰ _(D)=−88°

67.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 80 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₆H₃₀N₄O₄; MW: calc.: 450.54

MS: fnd.: 451.4

Starting from the corresponding starting compounds, which are mentionedor described explicitly below (compounds A28 to A40), the followingcompounds 68 to 80 are obtained according to the procedure as in Example18. If necessary, the cyclization reaction can be carried out in thepresence of a catalytic amount of a Lewis acid such e.g. tintetrachloride.

68. Acetic acid (2R,4aR,10bR)-9-ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₂H₂₆N₃O₄; MW: calc.: 395.46

MS: fnd.: 396.3

69. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₆H₂₈N₄O₄; MW: calc.: 460.54

MS: fnd.: 461.3

70. Acetic acid (2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridyl-5′-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₈H₃₅N₃O₄; MW: calc.: 477.61

MS: fnd.: 478.4

71.6-((2R,4aR,10bR)-2-Acetoxy-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-nicotinicacid methyl ester

EF: C₂₅H₂₈N₂O₆; MW: calc.: 452.51

MS: fnd.: 453.3

72. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₃H₂₇N₃O₅; MW: calc.: 425.49

MS: fnd.: 426.3

73. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(2,4,6-trimethoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₅H₃₁N₃O₇; MW: calc.: 485.54

MS: fnd.: 486.3

74. Acetic acid(2R,4aR,10bR)-6-(2,4-dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₄H₂₉N₃O₆; MW: calc.: 455.52

MS: fnd.: 456.3

75. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(5-methyl-pyrazin-2-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₃H₂₇N₃O₄; MW: calc.: 409.49

MS: fnd.: 410.3

76. Acetic acid(2R,4aR,10bR)-6-(2,6-dimethoxy-pyrimidin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₄H₂₉N₃O₆; MW: calc.: 455.52

MS: fnd.: 456.3

77. Acetic acid(2R,4aR,1013R)-9-ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₆H₂₈N₄O₄; MW: calc.: 460.55

MS: fnd.: 461.3

78. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₂H₂₅N₃O₄; MW: calc.: 395.46

MS: fnd.: 396.3

79. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(1-methyl-1H-benzotriazol-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₅H₂₈N₄O₄; MW: calc.: 448.53

MS: fnd.: 449.3

80. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

EF: C₂₇H₃₂N₄O₅; MW: calc.: 492.58

MS: fnd.: 493.4

81. (2S,4aS,10bS)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

The title compound can be obtained by chromatographical separation ofthe corresponding racemate (Example 1) using a column as described belowat the end of the chapter “Final compounds”.

EF: C₂₃H₂₈N₂O₅; MW: calc.: 412.49

MS: fnd.: 413.3

82.(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 83 the title compound is obtained in an analogousmanner as described for Example 1.

Alternatively, the title compound can be obtained by chromatographicalseparation of the corresponding racemate (Example 1) using a column asdescribed below at the end of the chapter “Final compounds”.

EF: C₂₃H₂₈N₂O₈; MW: calc.: 412.49

MS: fnd.: 413.3

83. Acetic acid (2R,4a R,10bR)-6-(2,6-dimethoxy-pyridn-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a, 10b-hexahydro-phenanthridin-2-ylester

Starting from compound A41 the title compound is obtained according tothe procedure as in Example 18. If necessary, the cyclization reactioncan be carried out in the presence of a catalytic amount of a Lewis acidsuch e.g. tin tetrachloride.

EF: C₂₈H₃₀N₂O₈; MW: calc.: 454.53

MS: fnd.: 455.3

84.(3SR,4aRS,10bRS)-8,9-Dimethoxy-6-pyridin-3-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-3-ol

Starting from compound 85 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₀H₂₂N₂O₃; MW: calc.: 338.41

MS: fnd.: 339.3

85. Acetic acid(3SR,4aRS,10bRS)-8,9-dimethoxy-6-pyridin-3-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-3-ylester

Starting from compound A42 the title compound is obtained according tothe procedure as in Example 18. If necessary, the cyclization reactioncan be carried out in the presence of a catalytic amount of a Lewis acidsuch e.g. tin tetrachloride.

EF: C₂₂H₂₄N₂O₄; MW: calc.: 380.45

MS: fnd.: 381.3

86.(2R,4aR,10bR)-6-(4-Chloro-2,6-dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,a3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from compound 87 the title compound is obtained in an analogousmanner as described for Example 1.

EF: C₂₃H₂₇ClN₂O₅; MW: calc.: 446.94

MS: fnd.: 447.3

87. Acetic acid(2R,4aR,10bR)-6-(4-chloro-2,6-dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

Starting from compound A41 the title compound is obtained according tothe procedure as in Example 83 as side product.

EF: C₂₅H₂₉ClN₂O₆; MW: calc.: 488.97

MS: fnd.: 489.2

Starting from the appropriate ester compounds, which are mentioned ordescribed explicitly below (compounds 96 to 103), or which can beprepared in a manner known to the person skilled in the art oranalogously or similarly to the examples described herein, the followingcompounds 88 to 95, and also further relevant, non-explicitly describedsimilar compounds are obtained according to the procedure as in Example1.

88.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methylsulfanyl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₆N₂O₃S

Calc.: 398.53

Found (MH⁺): 399.2

89.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(4-methyl-2-methylsulfanyl-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₇N₃O₃S

Calc.: 413.54

Found (MH⁺): 414.2

90.(2R,4aR,10bR)-6-(5-Chloro-2-methylsulfanyl-pyrimidin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₁H₂₄ClN₃O₃S

Calc.: 433.96

Found (MH⁺): 434.2 and 436.2

91.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₆N₂O₄

Calc.: 382.46

Found (MH⁺): 383.2

92.5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one

C₂₂H₂₆N₂O₄

Calc.: 382.46

Found (MH⁺): 383.2

93.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₆N₂O₄

Calc.: 382.46

Found (MH⁺): 383.3

94.(2R,4aR,10bR)-6-(4-Chloro-2-dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₇ClN₄O₃

Calc.: 430.94

Found (MH⁺): 431.3 and 433.2

95.(2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₃H₃₀N₄O₄

Calc.: 426.52

Found (MH⁺): 427.3

Starting from the corresponding starting compounds, which are mentionedor described explicitly below (compounds A43 to A50), the followingcompounds 96 to 103 are obtained according to the procedure as inExample 18. If necessary, the cyclization reaction can be carried out inthe presence of a catalytic amount of a Lewis acid such e.g. tintetrachloride.

96. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(2-methylsulfanyl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₈N₂O₄8

Calc.: 440.57

Found (MH⁺): 441.2

97. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(4-methyl-2-methylsulfanyl-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₃N₃O₄S

Calc.: 455.58

Found (MH⁺): 456.2

98. Acetic acid(2R,4aR,10bR)-6-(5-chloro-2-methylsulfanyl-pyrimidin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₃H₂₆ClN₃O₄S

Calc.: 476.00

Found (MH⁺): 476.2 and 478.1

99. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(2-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₈N₂O₃

Calc.: 424.50

Found (MH⁺): 425.3

100. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₈N₂O₅

Calc.: 424.50

Found (MH⁺): 425.3

101. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₈N₂O₅

Calc.: 424.50

Found (MH⁺): 425.2

102. Acetic acid(2R,4aR,10bR)-6-(4-chloro-2-dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

The title compound is obtained from compound A50 under the cyclizationconditions used.

C₂₄H₂₃ClN₄O₄

Calc.: 472.98

Found (MH⁺): 473.3 and 475.2

103. Acetic acid(2R,4aR,10bR)-6-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₅H₃₂N₄O₅

Calc.: 468.56

Found (MH⁺): 469.3

Starting from the appropriate ester compounds, which are mentioned ordescribed explicitly below (compounds 111 to 117), or which can beprepared in a manner known to the person skilled in the art oranalogously or similarly to the examples described herein, the followingcompounds 104 to 110 can be obtained according to the procedure as inExample 1.

104.(2R,4aR,10bR)-6-(4,6-Diethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₅H₃₂N₂O₅

Calc.: 440.54

Found (MH⁺): 441.3

105.(2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₃H₂₈N₂O₅

Calc.: 412.49

Found (MH⁺): 413.3

106.(2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₈N₄O₃

Calc.: 396.49

Found (MH⁺): 397.3

107.(2R,4aR,10bR)-6-(5,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₃H₂₈N₂O₅

Calc.: 412.49

108.(2R,4aR,10bR)-9-Ethoxy-6-(5-ethoxy-6-methoxy-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₄H₃₀N₂O₅

Calc.: 426.52

109.(2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methylsulfanyl-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₁H₂₅N₃O₃S

Calc.: 399.52

110. 5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6yl)-1-methyl-1H-pyrimidin-2-one

C₂₁H₂₅N₃O₄

Calc.: 383.45

Starting from the corresponding starting compounds, which are mentionedor described explicitly below (compounds A51 to A57), the followingcompounds 111 to 117 can be obtained according to the procedure as inExample 18. If necessary, the cyclization reaction can be carried out inthe presence of a catalytic amount of a Lewis acid such e.g. tintetrachloride.

111. Acetic acid(2R,4aR,10bR)-6-(4,6-diethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₇H₃₄N₂O₆

Calc.: 482.58

Found (MH⁺): 483.3

112. Acetic acid(2R,4aR,10bR)-6-(4,6-dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₅H₃₀N₂O₆

Calc.: 454.53

Found (MH⁺): 455.3

113. Acetic acid(2R,4aR,10bR)-6-(2-dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₃₀N₄O₄

Calc.: 438.53

Found (MH⁺): 439.3

114. Acetic acid(2R,4aR,10bR)-6-(5,6-dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₅H₃₀N₂O₆

Calc.: 454.53

115. Acetic acid(2R,4aR,10bR)-9-ethoxy-6-(5-ethoxy-6-methoxy-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₆H₃₂N₂O₆

Calc.: 468.55

116. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(2-methylsulfanyl-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₃H₂₇N₃O₄S

Calc.: 441.55

117. Acetic acid(2R,4aR,10bR)-9-ethoxy-8-methoxy-6-(1-methyl-2-oxo-1,2-dihydro-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₃H₂₇N₃O₆

Calc.: 425.49

Starting from the appropriate ester compounds, which are mentioned ordescribed explicitly below (compounds 121 to 123), or which can beprepared in a manner known to the person skilled in the art oranalogously or similarly to the examples described herein, the followingcompounds 118 to 120 can be obtained according to the procedure as inExample 1.

118.(2R,4aR,10bR)-9-Ethoxy-6-(6-hydroxy-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₁H₂₄N₂O₄

Calc.: 368.44

Found (MH⁺): 369.3

119.(2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂2H₂₇N₃O₅

Calc.: 413.48

Found (MH⁺): 414.3

120.(2R,4aR,10bR)-6-(4,6-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₇N₃O₅

Calc.: 413.48

Found (MH⁺): 414.3

Starting from the corresponding starting compounds, which are mentionedor described explicitly below (compounds A58 to A60), the followingcompounds 121 to 123 can be obtained according to the procedure as inExample 18. If necessary, the cyclization reaction can be carried out inthe presence of a catalytic amount of a Lewis acid such e.g. tintetrachloride.

121. Acetic acid(2R,4aR,10bR)-9-ethoxy-6-(6-hydroxy-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₃H₂₆N₂O₆

Calc.: 410.47

Found (MH⁺): 411.3

122. Acetic acid(2R,4aR,10bR)-6-(3,6-dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₉N₃O₆

Calc.: 455.52

Found (MH⁺): 456.3

123. Acetic acid(2R,4aR,10bR)-6-(4,6-dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₉N₃O₆

Calc.: 455.52

Found (MH⁺): 456.3

Starting from the appropriate ester compounds, which are mentioned ordescribed explicitly below (compounds 143 to 160), or which can beprepared in a manner known to the person skilled in the art oranalogously or similarly to the examples described herein, the followingcompounds 124 to 142 can be obtained according to the procedure as inExample 1.

124.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-pyridin-4-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₁H₂₄N₂O₃

Calc.: 352.44

Found (MH+): 353.3

125.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-pyridin-3-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₁H₂₄N₂O₃

Calc.: 352.44

Found (MH+): 353.3

126.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₅H₃₁N₃O₄

Calc.: 437.54

Found (MH+): 438.4

127.(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-6-(2,6-dimethoxy-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₄F₂N₂O₅

Calc.: 434.44

Found (MH+): 435.3

128.(2RS,4aRS,10bRS)-8-(1,1-Difluoro-methoxy)-6-(2,6-dimethoxy-pyridin-3-yl)-9-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₄F₂N₂O₅

Calc.: 434.44

Found (MH+): 435.2

129.(2RS,4aRS,10bRS)-6-Benzo[1,2,5]oxadiazol-5-yl-8-(1,1-difluoro-methoxy)-9-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₁H₁₉F₂N₃O₄

Calc.: 415.4

Found (MH+): 416.3

130.(2RS,4aRS,10bRS)-6-(2,6-Dimethoxy-pyrimidin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₇N₃O₅

Calc.: 413.48

Found (MH+): 414.2

131.(2RS,4aRS,10bRS)-6-(5-Chloro-2,6-bis-dimethylamino-pyrimidin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₄H₈₂ClN₅O₃

Calc.: 474.01

Found (MH+): 474.2/476.3

132.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₀H₂₃N₃O₃

Calc.: 353.42

Found (MH+): 354.2

133.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₀H₂₃N₃O₃

Calc.: 353.42

Found (MH+): 354.3

134.(2RS,4aRS,10bRS)-6-(5-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₅H₂₃ClN₂O₄

Calc.: 456.97

Found (MH+): 457.3/459.3

135.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₄H₂₆N₄O₃

Calc.: 418.5

Found (MH+): 419.3

136.(2RS,4aRS,10bRS)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₄H₂₆N₄O₃

Calc.: 418.5

Found (MH+): 419.2

137.(2RS,4aRS,10bRS)-6-Benzo[1,2,3]thiadiazol-5-yl-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₃N₃O₃S

Calc.: 409.51

Found (MH+): 410.1

138.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₇H₃₅N₃O₃

Calc.: 449.6

Found (MH+): 450.2

139.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₂H₂₆N₂O₄

Calc.: 382.46

Found (MH+): 383.2

140. (2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-(1-methyl-1H-benzotriazol-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₃H₂₆N₄O₃

Calc.: 406.49

Found (MH+): 407.2

141.(2RS,4aRS,10bRS)-9-Ethoxy-8-methoxy-6-quinoxalin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₄H₂₅N₃O₃

Calc.: 403.49

Found (MH+): 404.2

142.(2RS,4aRS,10bRS)-6-(3-Chloro-2,6-dimethoxy-pyridin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

C₂₃H₂₇ClN₂O₅

Calc.: 446.94

Found (MH+): 447.3

Starting, unless otherwise mentioned, from the corresponding startingcompounds, which can be prepared in a manner known to the person skilledin the art—analogously or similarly to the starting compounds describedherein below, the following compounds 143 to 160 can be obtainedaccording to the procedure as in Example 18. If necessary, thecyclization reaction can be carried out in the presence of a catalyticamount of a Lewis acid such e.g. tin tetrachloride.

143. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-pyridin-4-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₃H₂₆N₂O₄

Calc.: 394.47

Found (MH+): 395.3

144. Acetic acid(2RS,4aRS,1013RS)-9-ethoxy-8-methoxy-6-pyridin-3-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₃H₂₆N₂O₄

Calc.: 394.47

Found (MH+): 395.3

145. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₇H₃₃N₃O₅

Calc.: 479.58

Found (MH+): 480.4

146. Acetic acid(2RS,4aRS,10bRS)-9-(1,1-difluoro-methoxy)-6-(2,6-dimethoxy-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₆F₂N₂O₆

Calc.: 476.48

Found (MH+): 477.4

147. Acetic acid(2RS,4aRS,10bRS)-8-(1,1-difluoro-methoxy)-6-(2,6-dimethoxy-pyridin-3-yl)-9-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₆F₂N₂O₆

Calc.: 476.48

Found (MH+): 477.3

148. Acetic acid(2RS,4aRS,10bRS)-6-benzo[1,2,5]oxadiazol-5-yl-8-(11-difluoro-methoxy)-9-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester 149. Acetic acid (2RS,4aRS,10bRS)-6-(2,6-dimethoxy-pyrimidin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₃N₃O₆

Calc.: 455.52

Found (MH+): 456.2

150. Acetic acid(2RS,4aRS,10bRS)-6-(5-chloro-2,6-bis-dimethylamino-pyrimidin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

The title compound is obtained from acetic acid(1RS,3RS,4RS)-4-{[1-(bis-dimethylamino-pyrimidin-4-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester under the cyclization conditions used.

C₂₆H₃₄ClN₅O₄

Calc.: 516.04

Found (MH+): 516.3/518.3

151. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₂H₂₅N₃O₄

Calc.: 395.46

Found (MH+): 396.2

152. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₂H₂₅N₃O₄

Calc.: 395.46

Found (MH+): 396.2

153. Acetic acid(2RS,4aRS,10bRS)-6-(5-chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

The title compound is obtained from acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-methanoyl]-amino}-cyclohexylester under the cyclization conditions used.

C₂₇H₃₁ClN₂O₅

Calc.: 499.01

Found (MH+): 499.2/501.2

164. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₈H₂₈N₄O₄

Calc.: 460.54

Found (MH+): 461.3

155. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₆H₂₈N₄O₄

Calc.: 460.54

Found (MH+): 461.3

156. Acetic acid(2RS,4aRS,10bRS)-6-benzo[1,2,3]thiadiazol-5-yl-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₅N₃O₄S

Calc.: 451.55

Found (MH+): 452.1

157. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₉H₃₇N₃O₄

Calc.: 491.64

Found (MH+): 492.3

158. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-(2-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₄H₂₈N₂O₅

Calc.: 424.5

Found (MH+): 425.2

159. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-(1-methyl-1H-benzotriazol-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₅H₂₈N₄O₄

Calc.: 448.53

Found (MH+): 449.2

160. Acetic acid(2RS,4aRS,10bRS)-9-ethoxy-8-methoxy-6-quinoxalin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₆H₂₇N₃O₄

Calc.: 445.52

Found (MH+): 446.3

Starting from the appropriate ester compounds, which are mentioned ordescribed explicitly below (compounds 163 to 164), or which can beprepared in a manner known to the person skilled in the art oranalogously or similarly to the examples described herein, the followingcompounds 161 to 162 can be obtained according to the procedure as inExample 1.

161.(2RS,4aRS,10bRS)-8-(1,1-Difluoro-methoxy)-9-methoxy-6-pyridin-3-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol162.(2RS,4aRS,10bRS)-8-(1,1-Difluoro-methoxy)-9-methoxy-6-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

Starting from the corresponding starting compounds, which can beprepared in a manner known to the person skilled in the art—analogouslyor similarly to the starting compounds described herein below, thefollowing compounds 163 to 164 can be obtained according to theprocedure as in Example 18. If necessary, the cyclization reaction canbe carried out in the presence of a catalytic amount of a Lewis acidsuch e.g. tin tetrachloride.

163. Acetic acid(2RS,4aRS,10bRS)-8-(1,1-difluoro-methoxy)-9-methoxy-6-pyridin-3-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

C₂₂H₂₂F₂N₂O₄

Calc.: 416.43

Found (MH+): 417.3

164. Acetic acid(2RS,4aRS,10bRS)-8-(1,1-difluoro-methoxy)-9-methoxy-6-(6-morpholin-4-yl-pyridin-3-0)-1,2,3,4,42,10b-hexahydro-phenanthridin-2-ylester

C₂₆H₂₉F₂N₃O₅

Calc.: 501.53

Found (MH+): 502.4

165.5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboxylicacid

Analogously as described for Example 35 acidic acid(2R,4aR,10bR)-6-(6-cyano-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester (compound 172) is converted in a first step into the correspondingimino ester5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidicacid methyl ester. In a second step, 443 mg (1.08 mmol) of5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidicacid methyl ester are dissolved in 3 ml of THF. A solution of 51 mg(2.16 mmol) LiOH.H₂O is added and the solution stirred at 60° C. for 18hrs. The pH is adjusted to 5 using phosphoric acid andDisodiumhydrogenphosphate. The solvent is removed and the solid residueextracted with chloroform/methanol. After filtering off and re-movingthe volatiles 350 mg (82%) of the title compound are obtained.

C₂₂H₂₄N₂O₆

Calc.: 396.45

Found (MH+): 397.2

166.(2S,4aS,10bS)-6-(2,6-Dimethoxy-pyridin-3-yl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

The title compound can be obtained by chromatographical separation ofthe corresponding racemate (Example 42) using a column as describedbelow at the end of the chapter “Final compounds”.

C₂₂H₂₆N₂O₆

Calc.: 398.46

Found (MH+): 399.3

167.(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol

The title compound can be obtained by chromatographical separation ofthe corresponding racemate (Example 42) using a column as describedbelow at the end of the chapter “Final compounds”.

C₂₂H₂₆N₂O₆

Calc.: 398.46

Found (MH+): 399.2

168. Acidic acid(2R,4aR,10bR)-6-(6-cyano-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

Starting from compound A61 the title compound can be obtainedanalogously to Example 44.

169.(38R,4aRS,10bRS)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-3-ol

Starting from compound 170 the title compound can be obtainedanalogously to Example 1.

170. Acetic acid(3SR,4aRS,10bRS)-6-(2,6-dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-3-ylester

Starting from the appropriate starting compounds mentioned below thetitle compound can be obtained analogously to example 85.

Starting from the appropriate compounds mentioned above and theappropriate acid the corresponding salts can be obtained, for example,according to the following general procedure, or analogously orsimilarly thereto:

About 1 g of the free base is solved in about 10 ml of a suitablesolvent at room temperature. To this solution 1.1 eq. of the appropriateacid is added in one portion under stirring. The mixture is stirred overnight while the salt precipitated. The salt is filtered off, washed withabout 2 ml of the suitable solvent and dried over night at about 50° C.in vacuo. Thus, for example, in the case of hydrochloric acid an etheror alcohol solvent (e.g. dioxane, THF, diethylether, methanol, ethanol,or the like), or in the case of organic acids, such as e.g. fumaric,tartaric or oxoglutaric acid, a ketone solvent (e.g. acetone) may besuitable.

The following salts are obtained according to the abovementionedprocedure or analogously or similarly thereto:

-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol hydrochloride-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    hydrochloride-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    hydrochloride-   (2R,4a    R,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol hydrochloride-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    hydrochloride-   (2R,4a    R,10bR)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    hydrochloride-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol hydrochloride-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    hydrochloride-   (2R,4a    R,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-m    ethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol hydrochloride-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    hydrochloride-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    hydrochloride-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    hydrochloride-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    hydrochloride-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    sulfate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    sulfate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    sulfate-   (2R,4aR,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    sulfate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    sulfate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    sulfate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    sulfate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    sulfate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    sulfate-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methanesulfonate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   (2R,4aR,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    methansulfonate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    methansulfonate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    methansulfonate-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    citrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    citrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    citrate-   (2R,4a    R,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol citrate-   (2R,4aR,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    citrate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    citrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    citrate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    citrate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    citrate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol citrate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    citrate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    citrate-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol L-tartrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-tartrate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    L-tartrate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    L-tartrate-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-tartrate; m.p.: fnd.: decomposition starting at 107° C.-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-tartrate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-tartrate-   (2R,4aR,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-tartrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-tartrate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-tartrate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-tartrate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-tartrate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-tartrate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    D-tartrate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    D-tartrate-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    meso-tartrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    meso-tartrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    mesa-tartrate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    mesa-tartrate-   (2R,4aR,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    meso-tartrate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    meso-tartrate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    meso-tartrate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    meso-tartrate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    meso-tartrate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    meso-tartrate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    meso-tartrate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    meso-tartrate-   (2R4a    R,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-malate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-malate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-malate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-malate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-malate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-malate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-malate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    D-malate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    D-malate-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,    2,3,4,4a,10b-hexahydro-phenanthridin-2-ol L-malate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    malate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-malate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-malate-   (2R,4a    R,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol L-malate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-malate-   (2R,4a R,10b    R)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-m    ethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol L-malate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    L-malate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    L-malate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    L-malate-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate; m.p.: fnd.: decomposition starting at 172° C.-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate-   (2R,4aR,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol fumarate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    fumarate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    fumarate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    fumarate-   (2R,4a R,    10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    maleinate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    maleinate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    maleinate-   (2R,4a R,    10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    maleinate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    maleinate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,1    b-hexahydro-phenanthridin-2-ol maleinate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    maleinate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-m    ethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol maleinate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,1    b-hexahydro-phenanthridin-2-ol maleinate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    maleinate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    maleinate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    maleinate-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate; m.p.: fnd.: decomposition starting at 110° C.-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate-   (2R,4aR,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol oxoglutarate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate-   (2R,4a    R,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol oxoglutarate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxoglutarate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    oxoglutarate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    oxoglutarate-   (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxalate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxalate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    Oxalate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxalate-   (2R,4aR,10bR)-9-Ethoxy-6-(6-imidazol-1-yl-pyridin-3-yl)-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxalate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxalate-   (2R,4aR,10bR)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxalate-   (2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    oxalate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    oxalate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    oxalate-   (2R,4a    R,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol D-gluconate-   (2R,4a    R,10bR)-9-Ethoxy-8-methoxy-6-pyrimidin-5-yl-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-gluconate-   (2R,4aR,10bR)-9-Ethoxy-8-methoxy-6-(6-pyrazol-1-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-gluconate-   (2R,4a    R,10bR)-9-Ethoxy-8-methoxy-6-(2-methoxy-pyrimidin-5-yl)-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol D-gluconate-   (2R,4aR,10bR)-6-(2,4-Dimethoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-gluconate-   (2R,4a R,10bR)-9-Ethoxy-8-methoxy-6-pyrazin-2-yl-1,2,3,4,4a,    10b-hexa hydro-phenanthridin-2-ol D-gluconate-   (2R,4aR,10bR)-6-(3,6-Dimethoxy-pyridazin-4-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-gluconate-   (2R,4aR,10b    R)-9-Ethoxy-8-methoxy-6-(6-methoxy-pyridin-3-yl)-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol D-gluconate-   (2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol    D-gluconate-   (2R,4a R,10b    R)-6-(4,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexa    hydro-phenanthridin-2-ol D-gluconate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one    D-gluconate-   5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyrimidin-2-one    D-gluconate

Optionally the abovementioned salts can be converted in a suitablesolvent with the aid of a suitable base into the free compounds, whichcan be isolated in a manner known per se.

Chromatographical Separation:

Alternatively to the above described synthesis procedures usingenantiomerically pure starting compounds, enantiomerically pure finalcompounds of formula I, in which either R41 or R51 is hydrogen, can beobtained from the corresponding racemates by chromatographicalseparation, which can be afforded with one or more of the followingchiral columns:

CHIRALPAK® AD-H 5 μm (250×20 mm), 25° C.,

heptane/2-propanol/diethylamine=90/10/0.1; 20 ml/min, detection at 340nm;

CHIRALPAK® AD 20 μm (285×110 mm), 30° C., acetonitrile/isopropanol=95:5;570 ml/min, detection at 250 nm or 280 nm;

CHIRALPAK® AD 20 μm (250×50 mm), ambient temperature,heptane/isopropanol=95:5, 120 ml/min, detection at 330 nm; or

CHIRALPAK® 50801 20 μm (250×50 mm), 25° C., methanol, 120 ml/min,detection at 330 nm.

Starting Materials

A1. Acetic acid(1RS,3RS,4RS)-4-{[1-(2,6-dimethoxy-pyridin-3-yl)methanoyl]amino}-3-(3-ethoxy-4-methoxyphenyl)cyclohexylester

555 mg of 2,6-dimethoxynicotinic acid and 581 mg ofN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are placedin a flask under nitrogen. 778 mg of acetic acid (1RS,3RS,4RS)-4-amino-3-(3-ethoxy-4-methoxyphenyl)cyclohexyl ester(compound B1) and 2 mg of 4-dimethylaminopyridine both as solution indichloromethane are added and the solution stirred for 1 h at 40° C.,than 42 h at room temperature. The reaction is quenched with 5 ml ofwater. After phase separation the organic layer is washed with 2.5 ml ofsaturated potassium hydrogencarbonate solution. After drying the organiclayer with magnesium sulfate the solvent is removed to give 1.227 g ofthe crude title compound which are used for the following step withoutfurther purification.

MW: calc.: 472.54 MS: fnd: 473.1

Starting from the appropriate commercially available or art-knownheteroaryl carboxylic acids and the appropriate compound B1, B2, B3, B4or B5 further relevant, non-explicitly described starting compoundsanalogous to compound A1, which are also used to give via theabovementioned cyclization step the compounds mentioned above, areobtained according to the procedure as in Example A1.

The following compounds can be prepared from the appropriate startingcompounds mentioned below and the appropriate commercially available orart-known heteroaryl carboxylic acids in a manner according to ExampleA1.

A2. Acetic acid(1RS,3RS,4RS)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(3-methyl-3H-imidazol-4-yl)-methanoyl]-amino}-cyclohexylester

MW: calc.: 415.49 MS: fnd: 416.1

A3. Acetic acid(1RS,3RS,4RS)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(2-pyridin-3-yl-thiazol-4-yl)-methanoyl]-amino}-cyclohexylester

MW: calc.: 495.60 MS: fnd: 496.0

A4. Acetic acid(1RS,3RS,4RS)-3-(3-ethoxy-4-methoxy-phenyl)-4-[(1-isoxazol-5-yl-methanoyl)-amino]-cyclohexyl ester

MW: calc.: 402.45 MS: fnd: 402.8

A5. Acetic acid(1RS,3RS,4RS)-3-(3,4-dimethoxy-phenyl)-4-[(1-pyridin-4-yl-methanoyl)-amino]-cyclohexylester

MW calc.: 398.46 MS: fnd: 399.2

A6. Acetic acid(1RS,3RS,4RS)-3-(3,4-dimethoxy-phenyl)-4-[(1-pyridin-3-yl-methanoyl)-amino]-cyclohexylester

MW calc.: 398.46 MS: fnd: 399.2

A7. Acetic acid(1RS,3RS,4RS)-3-(3,4-dimethoxy-phenyl)-4-{[1-(6-morpholin-4-yl-pyridin-3-yl)-methanoyl]-amino}cyclohexylester

MW calc.: 483.57 MS: fnd: 484.4

A8. Acetic acid(1RS,3RS,4RS)-4-[(1-benzo[1,2,5]oxadiazol-5-yl-methanoyl)-amino]-3-[3-(1,1-difluoro-methoxy)-4-methoxy-phenyl]-cyclohexylester

MW calc.: 475.45 MS: fnd: 475.9

A9. Acetic acid(1RS,3RS,4RS)-4-[(1-benzo[1,2,6]oxadiazol-5-yl-methanoyl)-amino]-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-cyclohexylester

MW calc.: 489.48 MS: fnd: 489.9

A10. Acetic acid(1RS,3RS,4RS)-4-[(1-benzo[1,2,6]oxadiazol-5-yl-methanoyl)-amino]-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-cyclohexylester

MW calc.: 475.45 MS: fnd: 476.0

A11. Acetic acid(1RS,3RS,4RS)-4-[(1-2,3-dihydro-benzo[1,4]dioxin-6-yl-methanoyl)-amino]-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

MW calc.: 469.54 MS: fnd: 470.1

A12. Acetic acid(1RS,3RS,4RS)-4-[(1-benzo[1,3]dioxol-5-yl-methanoyl)-amino]-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

MW calc.: 455.51 MS: fnd: 456.1

A13. Acetic acid(1RS,3RS,4RS)-4-[(1-benzothiazol-6-yl-methanoyl)-amino]-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

MW calc.: 468.58 MS: fnd: 469.0

A14. Acetic acid(1RS,3RS,4RS)-3-(3,4-dimethoxy-phenyl)-4-[(1-quinolin-6-yl-methanoyl)-amino]-cyclohexylester

MW calc.: 448.52 MS: fnd: 449.3

A15. Acetic acid(1RS,3RS,4RS)-4-[{1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanoyl]-amino}-3-(3,4-dimethoxy-phenyl)-cyclohexylester

MW calc.: 477.47 MS: fnd: 478.0

A16. Acetic acid(1RS,3RS,4RS)-4-[(1-benzo[1,2,5]oxadiazol-5-yl-methanoyl)-amino]-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

MW calc.: 453.50 MS: fnd: 454.0

A17. Acetic acid(1RS,3RS,4RS)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(1-methyl-1H-imidazol-2-yl)-methanoyl]-amino}-cyclohexylester

MW calc.: 415.49 MS: fnd: 416.1

A18. Acetic acid(1RS,3RS,4RS)-4-{[1-(6-cyano-pyridin-3-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A19. Acetic acid(1RS,3RS,4RS)-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-4-{[1-(2,6-dimethoxy-pyridin-3-yl)-methanoyl]-amino}-cyclohexylester

MW calc.: 508.52 MS: fnd: 509.1

A20. Acetic acid(1RS,3RS,4RS)-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-4-{[1-(2-methoxy-pyridin-3-yl)-methanoyl]-amino}-cyclohexylester

MW calc.: 478.50 MS: fnd: 479.1

A21. Acetic acid(2RS,4aRS,10bRS)-9-(2,2-difluoro-ethoxy)-8-methoxy-6-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ylester

MW calc.: 533.58 MS: fnd: 534.3

A22. Acetic acid(1RS,3RS,4RS)-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-4-[(1-pyridin-3-yl-methanoyl)-amino]-cyclohexylester

MW calc.: 448.47

A23. Acetic acid(1RS,3RS,4RS)-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-4-{[1-(2,6-dimethoxy-pyrimidin-4-yl)-methanoyl]-amino}-cyclohexylester

MW calc.: 509.51

A24. Acetic acid(1RS,3RS,4RS)-3-[4-(2,2-difluoro-ethoxy)-3-methoxy-phenyl]-4-{[1-(2,6-dimethoxy-pyridin-3-yl)-methanoyl]-amino}-cyclohexylester

MW calc.: 508.52 MS: fnd: 509.2

A25. Acetic acid(1RS,3RS,4RS)-3-(3,4-dimethoxy-phenyl)-4-{[1-(2,6-dimethoxy-pyridin-3-yl)-methanoyl]-amino}-cyclohexylester

MW calc.: 458.52 MS: fnd: 459.1

A26. Acetic acid(1RS,3RS,4RS)-4-{[1-(2,6-dimethoxy-pyridin-4-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

MW calc.: 472.54 MS: fnd: 473.1

A27. Acetic acid(1RS,3RS,4RS)-4-amino-3-(5-(2,2-difluoro-ethoxy)-2-[1-(2,6-dimethoxy-pyridin-4-yl)-methanoyl]-4-methoxy-phenyl)-cyclohexylester

MW calc.: 508.52

A28. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-[1-pyrimidin-5-yl-methanoyl)-amino]-cyclohexylester

MW calc.: 413.48 MS: fnd: 414.1

A29. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(6-pyrazol-1-yl-pyridin-3-yl)-methanoyl]-amino}-cyclohexylester

MW calc.: 478.55

A30. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-[(1-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-yl-methanoyl)-amino]-cyclohexylester

MW calc.: 495.62 MS: fnd: 496.2

A31.6-[(1R,2R,4R)-4-Acetoxy-2-(3-ethoxy-4-methoxy-phenyl)-cyclohexylcarbamoyl]-nicotinicacid methyl ester

MW calc.: 470.53 MS: fnd: 471.2

A32. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(2-methoxy-pyrimidin-5-yl)-methanol]-amino}-cyclohexylester

MW calc.: 443.50 MS: fnd: 444.2

A33. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(2,4,6-trimethoxy-pyrimidin-5-yl)-methanoyl]-amino}cyclohexylester

MW calc.: 503.65 MS: fnd: 504.2

A34. Acetic acid(1R,3R,4R)-4-{[1-(2,4-dimethoxy-pyrimidin-5-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

MW calc.: 473.53 MS: fnd: 474.2

A35. Acetic acid(1R,3R,4R)-4-([1-(2,4-dimethoxy-pyrimidin-5-yl)-methanoyl]-amino)-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

MW calc.: 427.50 MS: fnd: 428.2

A36. Acetic acid(1R,3R,4R)-4-([1-(2,6-dimethoxy-pyrimidin-4-yl)-methanoyl]-amino)-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

MW calc.: 473.53 MS: fnd: 474.1

A37. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(6-imidazol-1-yl-pyridin-3-yl)-methanoyl]-amino}cyclohexylester

MW calc.: 478.55 MS: fnd: 479.3

A38. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-[(1-pyrazin-2-yl-methanoyl)-amino]-cyclohexylester

MW calc.: 413.48 MS: fnd: 414.2

A39. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-[(1-pyrazin-2-yl-methanoyl)-amino]-cyclohexylester

MW calc.: 466.54

A40. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-([1-(4-methoxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanoyl]-amino)-cyclohexylester

MW calc.: 510.60 MS: fnd: 511.2

A41. Acetic acid(1R,3R,4R)-4-{[1-(2,6-dimethoxy-pyridin-3-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

MW calc.: 472.54 MS: fnd: 473.2

A42. Acetic acid(1SR,3RS,4RS)-4-(3,4-dimethoxy-phenyl)-3-[(1-pyridin-3-yl-methanoyl)-amino]-cyclohexylester

MW calc.: 398.46 MS: fnd: 399.2

A43. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-([1-(2-methylsulfanyl-pyridin-3-yl)-methanoyl]-amino)-cyclohexylester A44. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(4-methyl-2-methylsulfanyl-pyrimidin-5-yl)-methanoyl]-amino}-cyclohexylester A45. Acetic add(1R,3R,4R)-4-{[1-(5-chloro-2-methylsulfanyl-pyrimidin-4-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A46. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(2-methoxy-pyridin-3-yl)-methanoyl]-amino}-cyclohexylester A47. Acetic add(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)methanoyl]-amino}-cyclohexyl ester A48. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(6-methoxy-pyridin-3-yl)-methanoyl]-amino}-cyclohexylester A49. Acetic acid(1R,3R,4R)-4-{[1-(2-dimethylamino-4-oxo-1,6-dihydro-pyrimidin-5-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A50. Acetic acid(1R,3R,4R)-4-{[1-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A51. Acetic acid(1R,3R,4R)-4-{[1-(4,6-diethoxy-pyridin-3-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A52. Acetic acid(1R,3R,4R)-4-{[1-(4,6-dimethoxy-pyridin-3-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A53. Acetic acid(1R,3R,4R)-4-{[1-(2-dimethylamino-pyrimidin-5-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A54. Acetic acid(1R,3R,4R)-4-{[1-(5,6-dimethoxy-pyridin-3-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A55. Acetic acid(1R,3R,4R)-4-{[1-(5-ethoxy-6-methoxy-pyridin-3-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A56. Acetic acid(1R,3R,4R)-4-{[1-(2-methylsulfanyl-pyrimidin-5-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester A57. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(1-methyl-2-oxo-1,2-dihydro-pyrimidin-5-yl)-methanoyl]-amino}-cyclohexylester A58. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(6-hydroxy-pyridin-3-yl)-methanoyl]-amino}-cyclohexylester A59. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{[1-(3,6-dimethoxy-pyridazin-4-yl)-methanoyl]-amino}-cyclohexylester A60. Acetic acid(1R,3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-4-{([1-(4,6-dimethoxy-pyrimidin-5-yl)-methanoyl]-amino}-cyclohexylester A61. Acetic acid(1R,3R,4R)-4-{[1-(6-cyano-pyridin-3-yl)-methanoyl]-amino}-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

Further relevant starting compounds for the final examples mentionedabove can be prepared from the appropriate starting compounds mentionedbelow and the appropriate commercially available or art-known heteroarylcarboxylic acids in a manner according to Example A1.

B1. Acetic acid(1RS,3RS,4RS)-4-amino-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexyl ester

Starting from compound C1 mentioned below, the title compound isobtained analogously to the procedure as in Example B2.

EF: C₁₇H₂₅NO₄; MW: 307.39

MS: 308.0 (MH⁺)

B1a. Acetic acid(1R,3R,4R)-4-amino-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexyl ester

24.0 g (55.0 mmol) of the pyroglutamate of the title compound (compoundBib) are suspended in 150 ml of water, 100 ml of dichloromethane areadded, then saturated KHCO₃-solution until the gas evolution ceased.After phase separation, reextraction of the water layer and drying thecombined organic layers with sodium sulfate the solvent is removed togive 16.9 g of the salt-free title compound. Analytical ColumnChromatography (CHIRALPAK AD-H 250×4.6 mm 5μ No.ADHOCE-DB030, Eluent:n-Hexan/iPrOH=80/20 (v/v)+0.1% Diethylamine): Retention Time: 6.54 min

B1b. Acetic acid(1R,3R,4R)-4-amino-3-(3-ethoxy-4-methoxy-phenyl)-cyclohexyl ester, omewith L-pyroglutamic acid

Solution A: 55.2 g (180 mmol) of racemic acetic acid (1RS,3RS,4RS)-4-amino-3-(3-ethoxy-4-methoxy-phenyl )-cyclohexylester(compound 131) are dissolved in 540 ml of isopropyl acetate.

Solution B: 18.6 g (144 mmol) of L-pyroglutamic acid are dissolved in260 ml of isopropanol under heating, then 290 ml of isopropyl acetate isadded carefully.

Solution B is added to solution A and left for 48 hours. The solid isfiltered off and washed with a little isopropyl acetate to give afterdrying 32.48 g colorless crystals with a ratio of the enantiomers of97:3 in favour of the title compound.

M.p.: 165-167° C.

B2. Acetic acid (1RS,3RS,4RS)-4-amino-3-(3,4-dimethoxyphenyl)cyclohexylester

A solution of 10.37 g of acetic acid(1RS,3RS,4RS)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexyl ester (compound02) in 240 ml of ethanol is added to a zinc-copper couple, prepared from16.8 g of zinc powder and 920 mg of copper (II) acetate monohydrate inacetic acid, the resulting suspension is refluxed and treated with 26 mlof acetic acid, 3.2 ml of water and 26 ml of ethanol. The resultingmixture is refluxed for further 15 min. The precipitate is filtered offwith suction and the solvent is removed. Chromatographical purificationon silica gel using a mixture of petroleum ether/ethyl ace-tate/triethylamine in the ratio 21711 and concentration of the correspondingeluate fractions afford 5.13 g (55% of theory) of the title compound asa pale brown oil.

R_(f)=0.35 (petroleum ether/ethyl acetate/triethylamine=2/7/1)

B3. Acetic acid(1RS,3RS,4RS)-4-amino-3-[4-(1,1-difluoro-methoxy)-3-methoxy-phenyl]-cyclohexylester

Starting from compound C3 mentioned below, the title compound isobtained analogously to the procedure as in Example B2.

EF: C₁₆H₂₁F₂NO₄; MW: 329.35

MS: 330.0 (MH⁺)

B4. Acetic acid(1RS,3RS,4RS)-4-amino-3-[3-(1,1-difluoro-methoxy)-4-methoxy-phenyl]-cyclohexylester

Starting from compound C4 mentioned below, the title compound isobtained analogously to the procedure as in Example B2.

EF: C₁₆H₂₁F₂NO₄; MW: 329.35

MS: 330.0 (MH⁺)

B5. Acetic acid(1RS,3RS,4RS)-4-amino-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-cyclohexylester

Starting from compound C5 mentioned below, the title compound isobtained analogously to the procedure as in Example B2.

B5a. Acetic acid(1R,3R,4R)-4-amino-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-cyclohexylester

The title compound is obtained from its pyroglutamate salt (compoundB5b) analogously as described for compound B1a using sodiumhydrogencarbonate solution.

B5b. Acetic acid(1R,3R,4R)-4-amino-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-cyclohexylester, salt with L-pyroglutamic acid

343 mg (1.00 mmol) of acetic acid(1RS,3RS,4RS)-4-amino-3-[3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-cyclohexylester (compound B5) are dissolved in 3 ml of isopropanol. A solution of103 mg (0.80 mmol) of L-pyroglutamic acid in 2 ml of isopropanol isadded. After filtering and drying 162 mg of the pyroglutamate areisolated with an enantiomeric ratio of 97:3 in favour of the titlecompound.

B6. Acetic acid(1SR,3RS,4RS)-3-amino-4-(3-ethoxy-4-methoxy-phenyl)-cyclohexyl ester

3.0 g (7.36 mmol) of acetic acid(1SR,3RS,4RS)-3-tert-butoxycarbonylamino-4-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester (compound C6) are dissolved in 6 ml of 4 M HCl in dioxane andstirred for 30 min. After removal of the solvent the residue isdissolved in dichloromethane and 25 ml of sat. Na—HCO₃ solution areadded carefully. After phase separation, reextraction of the water layerand drying of the combined organic layers (Na₂SO₄) the solvent isremoved to give 2.25 g of the title compound.

EF: C17H25N O4; MW: 307.39

MS: 308.1 (MH⁺)

B7. Acetic acid(1SR,3RS,4RS)-3-amino-4-(3,4-dimethoxy-phenyl)-cyclohexyl ester

The title compound can be obtained from compound C7 analogously asdescribed for compound B6.

C1. Acetic acid(1RS,3RS,4RS)-3-(3-ethoxy-4-methoxy-phenyl)-4-nitrocyclohexyl ester

Starting from compound D1 mentioned below, the title compound isobtained according to the procedure as in Example C2.

C2. Acetic acid (1RS,3RS,4RS)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexylester

10.18 g of (1 RS,3RS,4RS)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanol(compound D2) are dissolved in 100 ml of acetic anhydride and thesolution is heated to 100° C. for 1-2 h. After removal of the solvent,the residue is chromatographed on silica gel using a mixture ofpetroleum ether/ethyl acetate in the ratio 2/1. Concentration of thecorresponding eluate fractions furnish 10.37 g (89% of theory) of thetitle compound as an oil.

R_(f)=0.32 (petroleum ether/ethyl acetate=2/1)

Starting from the starting compounds mentioned below, the following areobtained according to the procedure as in Example C2:

C3. Acetic acid(1RS,3RS,4RS)-3-[4-(1,1-difluoro-methoxy)-3-methoxy-phenyl]-4-nitrocyclohexylester C4. Acetic acid(1RS,3RS,4RS)-3-[3-(1,1-difluoro-methoxy)-4-methoxy-phenyl]-4-nitrocyclohexylester C5. Acetic acid(1RS,3RS,4RS)-3-(3-(2,2-difluoro-ethoxy)-4-methoxy-phenyl]-4-nitrocyclohexylester C6. Acetic acid(1SR,3RS,4RS)-3-tert-butoxycarbonylamino-4-(3-ethoxy-4-methoxy-phenyl)-cyclohexylester

22.64 g (65 mmol) of [(1RS,6RS)-6-(3-ethoxy-4-methoxy-phenyl)-cyclohex-3-enyl]-carbamic acidtert-butyl ester (compound D6) are dissolved in 180 ml of THF and 50 mlof BH₃ (1 M solution in THF) are added dropwise (30 min). After stirringfor 2 h the mixture is cooled using an ice bath and a mixture of 30 mlof H₂O₂ (30%) and 60 ml of aqueous NaOH (3 M) is added. The mixture isstirred for 30 min at room temperature. 400 ml of water and 200 ml ofdichloromethane are added. After phase separation, reextraction of thewater layer and drying of the combined organic layers (Na₂SO₄) thesolvent is removed and the crude product (23.42 g, mixture of the twomentioned regioisomers 2:1 in favour of the title compound) is useddirectly without further purification.

The crude material from above then is dissolved in 50 ml of pyridine. 50mg of 4-dimethylaminopyridine and 60 ml of acetic anhydride are addedand the mixture stirred for 90 min at 100° C. The solvents and theacetic anhydride are removed (sat. NaHCO₃ solution). Purification bymeans of chromatography yields 9.4 g of the title compound as colorlessfoam.

EF: C22H33N O6; MW: 407.51

MS: 308.1 (MH⁺-Boc), 407.8 (MH⁺), 430.1 (Mna⁺)

C7. Acetic acid(1SR,3RS,4RS)-3-tert-butoxycarbonylamino-4-(3,4-dimethoxy-phenyl)-cyclohexylester

The title compound can be obtained from compound D7 analogously asdescribed for compound C6.

D1. (1 RS,3RS,4RS)-3-(3-Ethoxy-4-methoxy-phenyl)-4-nitrocyclohexanol

Starting from compound E1 mentioned below, the title compound isobtained according to the procedure as in Example D2.

D2. (1RS,3RS,4RS)-3-(3,4-Dimethoxyphenyl)-4-nitrocyclohexanol

10 g of (1RS,3RS,4SR)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanol(compound E2) are dissolved in 170 ml of absolute 1,2-dimethoxyethane.14.3 ml of a 30% solution of sodium methanolate in methanol are addeddropwise. After complete addition, stirring is continued for 10 min anda mixture consisting of 85% phosphoric acid and methanol is added topH 1. By adding of saturated potassium hydrogencarbonate solution theresulting suspension is neutralized. The mixture is diluted with waterand dichloromethane, the organic layer is separated and extracted withdichloromethane. The solvents are removed under reduced pressure toyield the title compound as a pale yellow oil, which crystallizes. Thetitle compound is used without further purification in the next step.

R_(f)=0.29 (petroleum ether/ethyl acetate=1/1)

M.p.: 126-127° C.

Starting from the appropriate starting compounds mentioned below, thefollowing are obtained according to the procedure as in Example D2:

D3. (1RS,3RS,4RS)-3-[4-(1,1-Difluoro-methoxy)-3-methoxy-phenyl]-4-nitrocyclohexanolD4. (1RS,3RS,4RS)-3-[3-(1,1-Difluoro-methoxy)-4-methoxy-phenyl]-4-nitrocyclohexanolD5. (1RS,3RS,4RS)-3-(3-(2,2-Difluoro-ethoxy)-4-methoxy-phenyl)-4-nitrocyclohexanolD6. [(1RS,6RS)-6-(3-Ethoxy-4-methoxy-phenyl)-cyclohex-3-enyl]-carbamicacid tert-butyl ester

Starting from (1RS,6RS)-6-(3-ethoxy-4-methoxy-phenyl)-cyclohex-3-enylamine (compound E6)the title compound is obtained analogously as described for compound D7.

EF: C20H29N O4; MW: 347.46,

MS: 370.1 (Mna⁺)

D7. [(1RS,6RS)-6-(3,4-Dimethoxy-phenyl)-cyclohex-3-enyl]-carbamic acidtert-butyl ester

15.18 g (65.06 mmol) of(±)-cis-6-(3,4-dimethoxyphenyl)-cyclohex-3-enylamine (compound E7) and14.21 g (65.11 mmol) of Boc₂O are stirred in dichloromethane for 2.5 h,then the solvent is removed and the residue crystallized fromethylacetate/n-heptane to give 19.1 g of the title compound.

EF: C19H27N O4; MW: 333.43,

MS: 334.2 (MH⁺)

E1. (1 RS,3RS,4SR)-3-(3-Ethoxy-4-methoxy-phenyl)-4-nitrocyclohexanol

Starting from compound F1 mentioned below, the title compound isobtained according to the procedure as in Example E2.

E2. (1 RS,3RS,4SR)-3-(3,4-Dimethoxyphenyl)-4-nitrocyclohexanol

Under nitrogen atmosphere 16.76 g of(3RS,4SR)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanone (compound F2) aredissolved in 300 ml of tetrahydrofurane, the solution is cooled to 78°C., and 75 ml of 1 M solution of potassium tri-sec-butylborohydride intetrahydrofurane is added dropwise. After stirring for further 1 h, amixture consisting of 30% hydrogeneperoxide solution and phosphatebuffer solution is added. Stirring is continued for further 10 min, thereaction mixture is diluted with 400 ml of ethyl acetate and the aqueouslayer is extracted with ethyl acetate, the combined organic phases areconcentrated to give a foam, which is purified by chromatography onsilica gel using a mixture of petroleum ether/ethyl acetate in the ratio1/1 to furnish 10.18 g (60% of theory) of the title compound.

EF: C₁₄H₁₉NO₆; MW: 281.31

MS: 299.1 (MNH₄ ⁺)

R_(f)=0.29 (petroleum ether/ethyl acetate=1/1)

M.p.: 139-141° C.

Starting from the appropriate starting compounds mentioned below, thefollowing are obtained according to the procedure as in Example E2:

E3.(1RS,3RS,4SR)-3-[4-(1,1-Difluoro-methoxy)-3-methoxy-phenyl]-4-nitrocyclohexanolE4.(1RS,3RS,4SR)-3-[3-(1,1-Difluoro-methoxy)-4-methoxy-phenyl]-4-nitrocyclohexanolE5.(1RS,3RS,4SR)-3-(3-(2,2-Difluoro-ethoxy)-4-methoxy-phenyl)-4-nitrocyclohexanolE6. (1RS,6RS)-6-(3-Ethoxy-4-methoxy-phenyl)-cyclohex-3-enylamine

Starting from2-ethoxy-1-methoxy-4-((1RS,6RS)-6-nitro-cyclohex-3-enyl)-benzene(compound F6) the title compound is obtained analogously as describedfor compound E7.

E7. (±)-cis-6-(3,4-Dimethoxyphenyl)-cyclohex-3-enylamine

40 g of (±)-cis-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene(compound F7) are dissolved in 400 ml of ethanol and 40 g of zinc powderare added. After heating to boiling temperature, 65 ml of glacial aceticacid are added dropwise. Afterwards, the reaction mixture is filtratedand concentrated. The residue is redissolved in diluted hydrochloricacid and extracted with toluene. The aqueous layer is alkalized using 6N solution of sodium hydroxide and extracted several times with toluene.The combined organic phases of the alkalic extraction are dried usingsodium sulfate and concentrated. The residue is chromatographed onsilica gel. 11.5 g of the title compound are obtained.

F1. (3RS,4SR)-3-(3-Ethoxy-4-methoxy-phenyl)-4-nitrocyclohexanone

Starting from compound G1 mentioned below, the title compound isobtained according to the procedure as in Example F2.

F2. (3RS,4SR)-3-(3,4-Dimethoxyphenyl)-4-nitrocyclohexanone

90.0 g of 3,4-dimethoxy-ω-nitrostyrene (compound G2), 90 ml of2-trimethylsilyloxy-1,3-butadiene and 180 ml of abs. Toluene are put inan autoclave, where the mixture is stirred at 140° C. for 2 days andthen cooled. After addition of 1000 ml of ethyl acetate, 300 ml of a 2 Nsolution of hydrochloric acid are dropped under stirring. The phases areseparated and the aqueous layer is extracted three times withdichloromethane. The combined organic extracts are washed with saturatedsodium hydrogencarbonate solution, dried over magnesium sulfate and thesolvents are removed under reduced pressure to give 150 g of the crudetitle compound. Further purification is carried out by chromatography onsilica gel using petroleum ether/ethyl acetate in the ratio 1/1 aseluent to give 81.5 g (67% of theory) of the pure title compound.

EF: C₁₄H₁₇N₅; MW: 279.30

MS: 279 (M⁺), 297.1 (MNH₄ ⁺)

R_(f)=0.47 (petroleum ether/ethyl acetate=1/1)

M.p.: 147-148° C.

Starting from the appropriate starting compounds mentioned below, thefollowing are obtained according to the procedure as in Example F2:

F3.(3RS,4SR)-3-[4-(1,1-Difluoro-methoxy)-3-methoxy-phenyl]-4-nitrocyclohexanoneF4.(3RS,4SR)-3-[3-(1,1-Difluoro-methoxy)-4-methoxy-phenyl]-4-nitrocyclohexanoneF5.(3RS,4SR)-3-(3-(2,2-Difluoro-ethoxy)-4-methoxy-phenyl)-4-nitrocyclohexanoneF6. 2-Ethoxy-1-methoxy-4-((1RS,6RS)-6-nitro-cyclohex-3-enyl)-benzene

Starting from 2-ethoxy-1-methoxy-4-((1RS,6SR)-6-nitro-cyclohex-3-enyl)-benzene (compound G6) the titlecompound is obtained analogously as described for compound F7.

F7. (±)-cis-1,2-Dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene

10.0 g of (±)-trans-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene(compound G7) and 20.0 g of potassium hydroxide are dissolved in 150 mlof ethanol and 35 ml of dimethylformamide. A solution of 17.5 ml ofconc. Sulfuric acid in 60 ml of ethanol is then added dropwise such thatthe internal temperature does not exceed 4° C. After stirring for 1 h,the mixture is added to 1 l of ice water, the precipitate is filteredoff with suction, washed with water and dried, and the crude product isrecrystallized in ethanol. 8.6 g of the title compound of m.p. 82.5-84°C. are obtained.

G1. 3-Ethoxy-4-methoxy-ω-nitrostyrene

Starting from art-known staffing compounds, the title compound isobtained according to the procedure as in Example G2:

G2. 3,4-Dimethoxy-ω-nitrostyrene

207.0 g of 3,4-dimethoxybenzaldehyde, 100.0 g of ammonium acetate and125 ml of nitromethane are heated to boiling for 3-4 h in 1.0 l ofglacial acetic acid. After cooling in an ice bath, the precipitate isfiltered off with suction, rinsed with glacial acetic acid and petroleumether and dried. M.p.: 140-141° C.

Yield: 179.0 g.

Starting from starting compounds, which are art-known or which can beobtained analogously to art-known compounds or according to art-knownprocedures (such as e.g. as described in WO 95/01338 or analogously orsimilarly thereto) the following compounds are obtained according to theprocedure as in Example G2:

G3. 4-(1,1-Difluoro-methoxy)-3-methoxy-ω-nitrostyrene G4.3-(1,1-Difluoro-methoxy)-4-methoxy-ω-nitrostyrene G5.3-(2,2-Difluoro-ethoxy-4)-methoxy-ω-nitrostyrene

The title compound is obtained starting from3-(2,2-difluoro-ethoxy)-4-methoxy-benzaldehyde (compound H1) accordingto the procedure as in Example G2.

M.p.: 164-165° C.

G6. 2-Ethoxy-1-methoxy-4-((1RS,6SR)-6-nitro-cyclohex-3-enyl)-benzene

Starting from 3-ethoxy-4-methoxy-ω-nitrostyrene (compound G1) the titlecompound is obtained analogously as described for compound G7.

G7. (±)-trans-1,2-Dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene

50.0 g of 3,4-dimethoxy-ω-nitrostyrene (compound G2), and 1.0 g (9.1mmol) of hydroquinone are suspened in 200 ml of abs. Toluene and treatedat 70° C. with 55.0 g (1.02 mol) of liquid 1,3-butadiene. The mixture isstirred at 160° C. for 6 days in an autoclave and then cooled. Some ofthe solvent is removed on a rotary evaporator, and the resultingprecipitate is filtered off with suction and recrystallized in ethanol.M.p.: 113.5-115.5° C.

H1. 3-(2,2-Difluoro-ethoxy)-4-methoxy-benzaldehyde

10.04 g of isovanillin and 15.5 g of potassium carbonate are placed inan autoclave. 50 ml of DMF are added as well as 12.44 g of2-bromo-1,1-difluoroethane. The autoclave is closed and heated at 60° C.for 20 h. Then the solids are filtered off and washed with 120 ml ofDMF. About 120 ml of the solvent are distilled off and the residuepoured on 200 ml of ice/water, where the product precipitates. Afterstirring the slurry for 30 minutes the product is filtered off and driedto give 13.69 g of the desired product.

M.p.: 66-68° C.

Commercial Utility

The compounds according to the invention have useful pharmacologicalproperties which make them industrially utilizable. As selective cyclicnucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4),they are suitable on the one hand as bronchial therapeutics (for thetreatment of airway obstructions on account of their dilating action butalso on account of their respiratory rate- or respiratorydrive-increasing action) and for the removal of erectile dysfunction onaccount of their vascular dilating action, but on the other handespecially for the treatment of disorders, in particular of aninflammatory nature, e.g. of the airways (asthma prophylaxis), of theskin, of the intestine, of the eyes, of the CNS and of the joints, whichare mediated by mediators such as histamine, PAF (platelet-activatingfactor), arachidonic acid derivatives such as leukotrienes andprostaglandins, cytokines, interleukins, chemokines, alpha-, beta- andgamma-interferon, tumor necrosis factor (TNF) or oxygen free radicalsand proteases. In this context, the compounds according to the inventionare distinguished by a low toxicity, a good enteral absorption (highbioavailability), a large therapeutic breadth and the absence ofsignificant side effects.

On account of their PDE-inhibiting properties, the compounds accordingto the invention can be employed in human and veterinary medicine astherapeutics, where they can be used, for example, for the treatment andprophylaxis of the following illnesses: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of varying origin(bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD);dermatoses (especially of proliferative, inflammatory and allergic type)such as psoriasis (vulgaris), toxic and allergic contact eczema, atopiceczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in theanogenital area, alopecia areata, hypertrophic scars, discoid lupuserythematosus, follicular and widespread pyodermias, endogenous andexogenous acne, acne rosacea and other proliferative, inflammatory andallergic skin disorders; disorders which are based on an excessiverelease of TNF and leukotrienes, for example disorders of the arthritistype (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis andother arthritic conditions), disorders of the immune system (AIDS,multiple sclerosis), graft versus host reaction, allograft rejections,types of shock (septic shock, endotoxin shock, gram-negative sepsis,toxic shock syndrome and ARDS (adult respiratory distress syndrome)) andalso generalized inflammations in the gastrointestinal region (Crohn'sdisease and ulcerative colitis); disorders which are based on allergicand/or chronic, immunological false reactions in the region of the upperairways (pharynx, nose) and the adjacent regions (paranasal sinuses,eyes), such as allergic rhinitis/sinusitis, chronic rhinitis/sinusitis,allergic conjunctivitis and also nasal polyps; but also disorders of theheart which can be treated by PDE inhibitors, such as cardiacinsuffi-ciency, or disorders which can be treated on account of thetissue-relaxant action of the PDE inhibitors, such as, for example,erectile dysfunction or colics of the kidneys and of the ureters inconnection with kidney stones. In addition, the compounds of theinvention are useful in the treatment of diabetes insipidus andconditions associated with cerebral metabolic inhibition, such ascerebral senility, senile dementia (Alzheimer's disease), memoryimpairment associated with Parkinson's disease or multiin-farctdementia; and also illnesses of central nervous system, such asdepressions or arterioscle-rotic dementia; as well as for enhancingcognition. Yet in addition, the compounds of the invention are useful inthe treatment of diabetes mellitus, leukaemia and osteoporosis.

The invention further relates to a method for the treatment of mammals,including humans, which are suffering from one of the above mentionedillnesses. The method is characterized in that a therapeutically activeand pharmacologically effective and tolerable amount of one or more ofthe compounds according to the invention is administered to the illmammal.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions which areemployed for the treatment and/or prophylaxis of the illnessesmentioned.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions for treatingdisorders which are mediated by phosphodiesterases, in particularPDE4-mediated disorders, such as, for example, those mentioned in thespecification of this invention or those which are apparent or known tothe skilled person.

The invention also relates to the use of the compounds according to theinvention for the manufacture of pharmaceutical compositions having PDE4inhibitory activity.

The invention furthermore relates to pharmaceutical compositions for thetreatment and/or prophylaxis of the illnesses mentioned comprising oneor more of the compounds according to the invention.

The invention yet furthermore relates to compositions comprising one ormore compounds according to this invention and a pharmaceuticallyacceptable carrier. Said compositions can be used in therapy, such ase.g. for treating, preventing or ameliorating one or more of theabovementioned diseases.

The invention still yet furthermore relates to pharmaceuticalcompositions according to this invention having PDE, particularly PDE4,inhibitory activity.

Additionally, the invention relates to an article of manufacture, whichcomprises packaging material and a pharmaceutical agent contained withinsaid packaging material, wherein the pharmaceutical agent istherapeutically effective for antagonizing the effects of the cyclicnucleotide phosphodiesterase of type 4 (PDE4), ameliorating the symptomsof an PDE4-mediated disorder, and wherein the packaging materialcomprises a label or package insert which indicates that thepharmaceutical agent is useful for preventing or treating PDE4-mediateddisorders, and wherein said pharmaceutical agent comprises one or morecompounds of formula I according to the invention. The packagingmaterial, label and package insert otherwise parallel or resemble whatis generally regarded as standard packaging material, labels and packageinserts for pharmaceuticals having related utilities.

The pharmaceutical compositions are prepared by processes which areknown per se and familiar to the person skilled in the art. Aspharmaceutical compositions, the compounds according to the invention(=active compounds) are either employed as such, or preferably incombination with suitable pharmaceutical auxiliaries and/or excipients,e.g. in the form of tablets, coated tablets, capsules, cap-lets,suppositories, patches (e.g. as TTS), emulsions, suspensions, gels orsolutions, the active compound content advantageously being between 0.1and 95% and where, by the appropriate choice of the auxiliaries and/orexcipients, a pharmaceutical administration form (e.g. a delayed releaseform or an enteric form) exactly suited to the active compound and/or tothe desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries, excipients,carriers, vehicles, diluents or adju-vants which are suitable for thedesired pharmaceutical formulations on account of his/her expertknowledge. In addition to solvents, gel formers, ointment bases andother active compound excipients, for example antioxidants, dispersants,emulsifiers, preservatives, solubilizers, colorants, complexing agentsor permeation promoters, can be used.

The administration of the pharmaceutical compositions according to theinvention may be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdermal and rectal delivery. Oral delivery is preferred.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosepharmaceutical compositions which are suitable for topical application.For the production of the pharmaceutical compositions, the compoundsaccording to the invention (=active compounds) are preferably mixed withsuitable pharmaceutical auxiliaries and further proc-essed to givesuitable pharmaceutical formulations. Suitable pharmaceuticalformulations are, for example, powders, emulsions, suspensions, sprays,oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The pharmaceutical compositions according to the invention are preparedby processes known per se. The dosage of the active compounds is carriedout in the order of magnitude customary for PDE inhibitors. Topicalapplication forms (such as ointments) for the treatment of dermatosesthus contain the active compounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarly between0.01 and 3 mg per day. The customary dose in the case of systemictherapy (p.o. or i.v.) is between 0.003 and 3 mg/kg per day. In anotherembodiment, the dose for administration by inhalation is between 0.1 and3 mg per day, and the dose in the case of systemic therapy (p.o. ori.v.) is between 0.03 and 3 mg/kg per day.

Biological Investigations

The second messenger cyclic AMP (cAMP) is well-known for inhibitinginflammatory and immuno-competent cells. The PDE4 isoenzyme is broadlyexpressed in cells involved in the initiation and propagation ofinflammatory diseases (H Tenor and C Schudt, in PhosphodiesteraseInhibitors“, 21-40, The Handbook of Immunopharmacology”, Academic Press,1996), and its inhibition leads to an increase of the intracellular cAMPconcentration and thus to the inhibition of cellular activation (JESouness et al., Immunopharmacology 47: 127-162, 2000).

The antiinflammatory potential of PDE4 inhibitors in vivo in variousanimal models has been described (MM Teixeira, TiPS 18: 164-170, 1997).For the investigation of PDE4 inhibition on the cellular level (invitro), a large variety of proinflammatory responses can be measured.Examples are the su-peroxide production of neutrophilic (C Schudt etal., Arch Pharmacol 344: 682-690, 1991) or eosino-philic (A Hatzelmannet al., Brit J Pharmacol 114: 821-831, 1995) granulocytes, which can bemeasured as luminol-enhanced chemiluminescence, or the synthesis oftumor necrosis factor-α in mono-cytes, macrophages or dendritic cells(Gantner et al., Brit J Pharmacol 121: 221-231, 1997, and Pul-monaryPharmacol Therap 12: 377-386, 1999). In addition, the immunomodulatorypotential of PDE4 inhibitors is evident from the inhibition of T-cellresponses like cytokine synthesis or proliferation (DM Essayan, BiochemPharmacol 57: 965-973, 1999). Substances which inhibit the secretion ofthe afore-mentioned proinflammatory mediators are those which inhibitPDE4. PDE4 inhibition by the compounds according to the invention isthus a central indicator for the suppression of inflammatory processes.

Methods for Measuring Inhibition of PDE4 Activity

The PDE4B2 (GB no. M97515) was a gift of Prof. M. Conti (StanfordUniversity, USA). It was ampli-fied from the original plasmid (pCMV5)via PCR with primers Rb9 (5′-GCCAGCGTGCAAATAAT-GAAGG-3′) and Rb10(5′-AGAGGGGGATTATGTATCCAC 3′) and cloned into the pCR-Bac vector(Invitrogen, Groningen, NL).

The recombinant baculovirus was prepared by means of homologousrecombination in SF9 insect cells. The expression plasmid wascotransfected with Bac-N-Blue (Invitrogen, Groningen, NL) or Baculo-GoldDNA (Pharmingen, Hamburg) using a standard protocol (Pharmingen,Hamburg). Wt vi-rus-free recombinant virus supernatant was selectedusing plaque assay methods. After that, high-titre virus supernatant wasprepared by amplifying 3 times. PDE was expressed in SF21 cells byinfecting 2×10⁶ cells/ml with an MOI (multiplicity of infection) between1 and 10 in serum-free SF900 medium (Life Technologies, Paisley, UK).The cells were cultured at 28° C. for 48-72 hours, after which they werepelleted for 5-10 min at 1000 g and 4° C.

The SF21 insect cells were resuspended, at a concentration of approx.10⁷ cells/ml, in ice-cold (4° C.) homogenization buffer (20 mM Tris, pH8.2, containing the following additions: 140 mM NaCl, 3.8 mM KCl, 1 mMEGTA, 1 mM MgCl₂, 10 mM β-mercaptoethanol, 2 mM benzamidine, 0.4 mMPefablock, 10 μM leupeptin, 10 μM pepstatin A, 5 μM trypsin inhibitor)and disrupted by ultrasonication. The homogenate was then centrifugedfor 10 min at 1000×g and the supernatant was stored at 80° C. untilsubsequent use (see below). The protein content was determined by theBradford method (BioRad, Munich) using BSA as the standard.

PDE4B2 activity is inhibited by the said compounds in a modified SPA(scintillation proximity assay) test, supplied by Amersham Biosciences(see procedural instructions “phosphodiesterase[3H]cAMP SPA enzymeassay, code TRKQ 7090”), carried out in 96-well microtiter plates(MTP's). The test volume is 100 μl and contains 20 mM Tris buffer (pH7.4), 0.1 mg of BSA (bovine serum albumin)/ml, 5 mM Mg²⁺, 0.5 μM cAMP(including about 50,000 cpm of [3H]cAMP), 1 μl of the respectivesubstance dilution in DMSO and sufficient recombinant PDE (1000×gsupernatant, see above) to ensure that 10-20% of the cAMP is convertedunder the said experimental conditions. The final concentration of DMSOin the assay (1% v/v) does not substantially affect the activity of thePDE investigated. After a preincubation of 5 min at 37° C., the reactionis started by adding the substrate (cAMP) and the assay is incubated fora further 15 min; after that, it is stopped by adding SPA beads (50 μl).In accordance with the manufacturer's instructions, the SPA beads hadpreviously been resuspended in water, but were then diluted 1:3 (v/v) inwater; the diluted solution also contains 3 mM IBMX to ensure a completePDE activity stop. After the beads have been sedimented (>30 min), theMTP's are analyzed in commercially available luminescence detectiondevices. The corresponding IC₅₀ values of the compounds for theinhibition of PDE activity are determined from the concentration-effectcurves by means of non-linear regression.

Representative inhibitory values determined for the compounds accordingto the invention follow from the following table A, in which the numbersof the compounds correspond to the numbers of the Examples.

TABLE A Inhibition of the PDE4 activity Compound −log IC₅₀ (mol/l)  1The inhibitory values of these listed  2 compounds 1 to 16 are in therange  3 from 7.24 to 9.32  4  5  6  7  8  9 10 11 12 13 14 15 16 35 to40, 52, 53, 55 The inhibitory values of these listed to 67, 70 to 72,and compounds 35 to 40, 52, 53, 55 to 67, 82 70 to 72, and 82 are in therange from 6.91 to 9.17 86, 88 to 95, 98, The inhibitory values of theselisted 101, 102, 118, 119, compounds 86, 88 to 95, 98, 101, 124 to 127,129 to 102, 118, 119, 141, 145, 156, 158 124 to 127, 129 to 141, 145,156, 158 to 160, 165, and 167 to 160, 165, and 167 are in the range from7.02 to 9.4

The invention claimed is:
 1. A method of treating atopic eczema in apatient, comprising administering to said patient a compound of formulaIa*****

wherein R1 is methoxy, R2 is methoxy, ethoxy, difluoromethoxy or2,2-difluoroethoxy, R3 is hydrogen, R31 is hydrogen, R41 is hydrogen, R5is hydrogen, Har is substituted by R6 and R7, and is pyridinyl, in whichR6 is oxo, and R7 is methyl, or a pharmaceutically acceptable saltthereof.
 2. The method of treating atopic eczema in a patient accordingto claim 1, comprising administering to said patient a compound offormula Ia*****, wherein R1 is methoxy, R2 is methoxy, ethoxy,difluoromethoxy or 2,2-difluoroethoxy, R3 is hydrogen, R31 is hydrogen,R41 is hydrogen, R5 is hydrogen, Har is 1-methyl-1H-pyridin-2-one-5-yl,or a pharmaceutically acceptable salt thereof.
 3. The method of treatingatopic eczema in a patient according to claim 1, comprisingadministering to said patient a compound of formula Ia*****, wherein R1is methoxy, R2 is ethoxy, difluoromethoxy or 2,2-difluoroethoxy, R3 ishydrogen, R31 is hydrogen, R41 is hydrogen, R5 is hydrogen, Har is1-methyl-1H-pyridin-2-one-5-yl, or a pharmaceutically acceptable saltthereof.
 4. The method of treating atopic eczema in a patient accordingto claim 1, comprising administering to said patient a compound offormula Ia*****, which is selected from the group consisting of5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-oneand a pharmaceutically acceptable salt thereof.
 5. The method oftreating atopic eczema in a patient according to claim 1, comprisingadministering to said patient a compound of formula Ia*****, which is5-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-1-methyl-1H-pyridin-2-one.